Jane Salodof MacNeil

CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.

Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.

Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.

Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.

"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.

Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (2011 June 4;doi:10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:

• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).

• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).

Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.

Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.

Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.

Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.

Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.

"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.

The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.

Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.

Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.

Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.

Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies.

CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.

Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.

Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.

Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.

"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.

Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (2011 June 4;doi:10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:

• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).

• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).

Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.

Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.

Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.

Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.

Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.

"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.

The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.

Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.

Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.

Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.

Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies.

CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.

Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.

Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.

Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.

"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.

Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (2011 June 4;doi:10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:

• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).

• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).

Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.

Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.

Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.

Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.

Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.

"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.

The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.

Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.

Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.

Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.

Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies.

CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.

Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.

Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.

Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.

"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.

Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:

• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).

• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).

Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.

Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.

Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.

Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.

Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.

"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.

The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.

Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.

Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.

Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.

Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies. Dr. Davidson and Dr. Kensler disclosed no relevant conflicts of interest.

CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.

Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.

Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.

Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.

"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.

Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:

• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).

• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).

Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.

Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.

Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.

Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.

Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.

"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.

The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.

Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.

Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.

Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.

Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies. Dr. Davidson and Dr. Kensler disclosed no relevant conflicts of interest.

CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.

Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.

Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.

Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.

"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.

Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:

• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).

• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).

Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.

Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.

Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.

Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.

Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.

"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.

The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.

Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.

Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.

Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.

Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies. Dr. Davidson and Dr. Kensler disclosed no relevant conflicts of interest.

CHICAGO — A new chemotherapy regimen that starts children and young adults on 50 times the standard dose of methotrexate for high-risk B-precursor acute lymphoblastic leukemia leads to significantly fewer recurrences five years after treatment without an increase in toxicity.

A randomized phase III trial comparing the high-dose regimen to standard therapy was halted in January 2011 after an interim analysis found the 5-year event-free survival rate reached 82% with the new regimen vs. 75% with the old (P = .0006).

Pediatric oncologists began using the new high-dose regimen as standard practice "as soon as we stopped the protocol," Dr. Eric C. Larsen, principal investigator of the study, said at a press briefing June 3, on the opening day of the annual meeting of the American Society of Clinical Oncology. He will present the results June 5 in a plenary session featuring the most important research at the meeting.

Acute lymphoblastic leukemia (ALL) is the most common leukemia in children. Children with high-risk ALL have a high white blood count at diagnosis and/or are 10 years or more of age.

Although pediatric ALL has a high cure rate and the standard regimen had reduced relapses in the bone marrow over time, investigators were concerned that relapses in the central nervous system had not declined as much. Therefore, they sought a regimen with the potential for greater penetration of tumor cells in the central nervous system.

When the study was conceived 10 years ago, the investigators did not have a new drug or targeted therapy, however, said Dr. Larsen, director of the Maine Children’s Cancer Program and the division of pediatric hematology/oncology at the Barbara Bush Children’s Hospital at Maine Medical Center in Portland. Therefore, "rather than trying something brand new," they decided to try to optimize treatment with a drug that "had been around for awhile."

One of the earliest chemotherapy drugs, methotrexate promotes cancer cell death by preventing leukemia cells from using folate, an essential vitamin. Its use dates to 1947 when Dr. Sidney Farber induced the first remissions in children with ALL by giving them an early form of methotrexate called aminopterin. It is an essential component of treatment for pediatric ALL, but the optimal regimen was not resolved.

Dr. Richard Schilsky, a professor of medicine and chief of the section of hematology-oncology at the University of Chicago Pritzker School of Medicine, suggested oncologists treating adults have much to learn from how the investigators focused on an existing therapy. "The pediatric oncologists have recognized that to get optimal results in treating cancer you have to optimize the way cancer treatment is given," said Dr. Schilsky, a former ASCO president and moderator of the press briefing.

The Children’s Oncology Group AALL0232 trial started in 2004 and enrolled 3,154 newly diagnosed patients ages 1 to 30. Most pediatric ALL trials do not enroll patients older than 21 years of age, Dr. Larsen said in an interview, but current thinking suggests that young adult patients may do better on pediatric protocols.

At the time of the interim analysis, 2,426 patients had been randomized. About half the population in the interim analysis, 1,217 patients, was treated with a standard Capizzi regimen in which intravenous methotrexate is delivered at a starting dose of 100 mg/m² and escalated by 50 mg/m² every 10 days up to a maximum of 5 doses depending on the child’s ability to tolerate the medication. In this regimen methotrexate is followed by a second chemotherapy drug called asparaginase.

The other 1,209 patients were assigned to the high-dose arm, and received 5 g/m² – that is, 5,000 mg/m² of methotrexate biweekly in four doses.

Despite concerns that the high-dose regimen would lead to more toxicity, febrile neutropenia occurred less in the experimental arm of the trial: 5.2% vs. 8.2% in the standard arm (P = .005). Leucovorin rescue was available for patients on high-dose methotrexate, which may partially explain the lower incidence of neutropenia in this group. Acute neurotoxicity, osteonecrosis, and other clinically relevant side effects were not significantly different.

Investigators are not sure why the high-dose regimen is less toxic, but side effects with standard therapy may be more the result of the combination of drugs in the Capizzi regimen than of methotrexate itself, Dr. Larsen said.

A substudy is looking at the comparative costs of the two regimens, he added. Methotrexate is inexpensive, but the high-dose regimen requires hospitalization. This needs to be balanced against the cost of hospitalizing and treating with antibiotics the greater proportion of children developing febrile neutropenia, a serious toxicity, on the Capizzi regimen.

A new wrinkle, Dr. Larsen noted, is that the Children’s Oncology Group and the adult Cancer and Leukemia Group B are planning a joint trial comparing adult and children’s regimens for teens and young adults with ALL. It was scheduled to use the Capizzi regimen but needs to be reconsidered.

The National Institutes of Health provided funds for the trial. Two co-authors said they received research funding from Becton-Dickinson.

CHICAGO — A new chemotherapy regimen that starts children and young adults on 50 times the standard dose of methotrexate for high-risk B-precursor acute lymphoblastic leukemia leads to significantly fewer recurrences five years after treatment without an increase in toxicity.

A randomized phase III trial comparing the high-dose regimen to standard therapy was halted in January 2011 after an interim analysis found the 5-year event-free survival rate reached 82% with the new regimen vs. 75% with the old (P = .0006).

Pediatric oncologists began using the new high-dose regimen as standard practice "as soon as we stopped the protocol," Dr. Eric C. Larsen, principal investigator of the study, said at a press briefing June 3, on the opening day of the annual meeting of the American Society of Clinical Oncology. He will present the results June 5 in a plenary session featuring the most important research at the meeting.

Acute lymphoblastic leukemia (ALL) is the most common leukemia in children. Children with high-risk ALL have a high white blood count at diagnosis and/or are 10 years or more of age.

Although pediatric ALL has a high cure rate and the standard regimen had reduced relapses in the bone marrow over time, investigators were concerned that relapses in the central nervous system had not declined as much. Therefore, they sought a regimen with the potential for greater penetration of tumor cells in the central nervous system.

When the study was conceived 10 years ago, the investigators did not have a new drug or targeted therapy, however, said Dr. Larsen, director of the Maine Children’s Cancer Program and the division of pediatric hematology/oncology at the Barbara Bush Children’s Hospital at Maine Medical Center in Portland. Therefore, "rather than trying something brand new," they decided to try to optimize treatment with a drug that "had been around for awhile."

One of the earliest chemotherapy drugs, methotrexate promotes cancer cell death by preventing leukemia cells from using folate, an essential vitamin. Its use dates to 1947 when Dr. Sidney Farber induced the first remissions in children with ALL by giving them an early form of methotrexate called aminopterin. It is an essential component of treatment for pediatric ALL, but the optimal regimen was not resolved.

Dr. Richard Schilsky, a professor of medicine and chief of the section of hematology-oncology at the University of Chicago Pritzker School of Medicine, suggested oncologists treating adults have much to learn from how the investigators focused on an existing therapy. "The pediatric oncologists have recognized that to get optimal results in treating cancer you have to optimize the way cancer treatment is given," said Dr. Schilsky, a former ASCO president and moderator of the press briefing.

The Children’s Oncology Group AALL0232 trial started in 2004 and enrolled 3,154 newly diagnosed patients ages 1 to 30. Most pediatric ALL trials do not enroll patients older than 21 years of age, Dr. Larsen said in an interview, but current thinking suggests that young adult patients may do better on pediatric protocols.

At the time of the interim analysis, 2,426 patients had been randomized. About half the population in the interim analysis, 1,217 patients, was treated with a standard Capizzi regimen in which intravenous methotrexate is delivered at a starting dose of 100 mg/m² and escalated by 50 mg/m² every 10 days up to a maximum of 5 doses depending on the child’s ability to tolerate the medication. In this regimen methotrexate is followed by a second chemotherapy drug called asparaginase.

The other 1,209 patients were assigned to the high-dose arm, and received 5 g/m² – that is, 5,000 mg/m² of methotrexate biweekly in four doses.

Despite concerns that the high-dose regimen would lead to more toxicity, febrile neutropenia occurred less in the experimental arm of the trial: 5.2% vs. 8.2% in the standard arm (P = .005). Leucovorin rescue was available for patients on high-dose methotrexate, which may partially explain the lower incidence of neutropenia in this group. Acute neurotoxicity, osteonecrosis, and other clinically relevant side effects were not significantly different.

Investigators are not sure why the high-dose regimen is less toxic, but side effects with standard therapy may be more the result of the combination of drugs in the Capizzi regimen than of methotrexate itself, Dr. Larsen said.

A substudy is looking at the comparative costs of the two regimens, he added. Methotrexate is inexpensive, but the high-dose regimen requires hospitalization. This needs to be balanced against the cost of hospitalizing and treating with antibiotics the greater proportion of children developing febrile neutropenia, a serious toxicity, on the Capizzi regimen.

A new wrinkle, Dr. Larsen noted, is that the Children’s Oncology Group and the adult Cancer and Leukemia Group B are planning a joint trial comparing adult and children’s regimens for teens and young adults with ALL. It was scheduled to use the Capizzi regimen but needs to be reconsidered.

The National Institutes of Health provided funds for the trial. Two co-authors said they received research funding from Becton-Dickinson.

CHICAGO — A new chemotherapy regimen that starts children and young adults on 50 times the standard dose of methotrexate for high-risk B-precursor acute lymphoblastic leukemia leads to significantly fewer recurrences five years after treatment without an increase in toxicity.

A randomized phase III trial comparing the high-dose regimen to standard therapy was halted in January 2011 after an interim analysis found the 5-year event-free survival rate reached 82% with the new regimen vs. 75% with the old (P = .0006).

Pediatric oncologists began using the new high-dose regimen as standard practice "as soon as we stopped the protocol," Dr. Eric C. Larsen, principal investigator of the study, said at a press briefing June 3, on the opening day of the annual meeting of the American Society of Clinical Oncology. He will present the results June 5 in a plenary session featuring the most important research at the meeting.

Acute lymphoblastic leukemia (ALL) is the most common leukemia in children. Children with high-risk ALL have a high white blood count at diagnosis and/or are 10 years or more of age.

Although pediatric ALL has a high cure rate and the standard regimen had reduced relapses in the bone marrow over time, investigators were concerned that relapses in the central nervous system had not declined as much. Therefore, they sought a regimen with the potential for greater penetration of tumor cells in the central nervous system.

When the study was conceived 10 years ago, the investigators did not have a new drug or targeted therapy, however, said Dr. Larsen, director of the Maine Children’s Cancer Program and the division of pediatric hematology/oncology at the Barbara Bush Children’s Hospital at Maine Medical Center in Portland. Therefore, "rather than trying something brand new," they decided to try to optimize treatment with a drug that "had been around for awhile."

One of the earliest chemotherapy drugs, methotrexate promotes cancer cell death by preventing leukemia cells from using folate, an essential vitamin. Its use dates to 1947 when Dr. Sidney Farber induced the first remissions in children with ALL by giving them an early form of methotrexate called aminopterin. It is an essential component of treatment for pediatric ALL, but the optimal regimen was not resolved.

Dr. Richard Schilsky, a professor of medicine and chief of the section of hematology-oncology at the University of Chicago Pritzker School of Medicine, suggested oncologists treating adults have much to learn from how the investigators focused on an existing therapy. "The pediatric oncologists have recognized that to get optimal results in treating cancer you have to optimize the way cancer treatment is given," said Dr. Schilsky, a former ASCO president and moderator of the press briefing.

The Children’s Oncology Group AALL0232 trial started in 2004 and enrolled 3,154 newly diagnosed patients ages 1 to 30. Most pediatric ALL trials do not enroll patients older than 21 years of age, Dr. Larsen said in an interview, but current thinking suggests that young adult patients may do better on pediatric protocols.

At the time of the interim analysis, 2,426 patients had been randomized. About half the population in the interim analysis, 1,217 patients, was treated with a standard Capizzi regimen in which intravenous methotrexate is delivered at a starting dose of 100 mg/m² and escalated by 50 mg/m² every 10 days up to a maximum of 5 doses depending on the child’s ability to tolerate the medication. In this regimen methotrexate is followed by a second chemotherapy drug called asparaginase.

The other 1,209 patients were assigned to the high-dose arm, and received 5 g/m² – that is, 5,000 mg/m² of methotrexate biweekly in four doses.

Despite concerns that the high-dose regimen would lead to more toxicity, febrile neutropenia occurred less in the experimental arm of the trial: 5.2% vs. 8.2% in the standard arm (P = .005). Leucovorin rescue was available for patients on high-dose methotrexate, which may partially explain the lower incidence of neutropenia in this group. Acute neurotoxicity, osteonecrosis, and other clinically relevant side effects were not significantly different.

Investigators are not sure why the high-dose regimen is less toxic, but side effects with standard therapy may be more the result of the combination of drugs in the Capizzi regimen than of methotrexate itself, Dr. Larsen said.

A substudy is looking at the comparative costs of the two regimens, he added. Methotrexate is inexpensive, but the high-dose regimen requires hospitalization. This needs to be balanced against the cost of hospitalizing and treating with antibiotics the greater proportion of children developing febrile neutropenia, a serious toxicity, on the Capizzi regimen.

A new wrinkle, Dr. Larsen noted, is that the Children’s Oncology Group and the adult Cancer and Leukemia Group B are planning a joint trial comparing adult and children’s regimens for teens and young adults with ALL. It was scheduled to use the Capizzi regimen but needs to be reconsidered.

The National Institutes of Health provided funds for the trial. Two co-authors said they received research funding from Becton-Dickinson.

CHICAGO — A new chemotherapy regimen that starts children and young adults on 50 times the standard dose of methotrexate for high-risk B-precursor acute lymphoblastic leukemia leads to significantly fewer recurrences five years after treatment without an increase in toxicity.

A randomized phase III trial comparing the high-dose regimen to standard therapy was halted in January 2011 after an interim analysis found the 5-year event-free survival rate reached 82% with the new regimen vs. 75% with the old (P = .0006).

Pediatric oncologists began using the new high-dose regimen as standard practice "as soon as we stopped the protocol," Dr. Eric C. Larsen, principal investigator of the study, said at a press briefing June 3, on the opening day of the annual meeting of the American Society of Clinical Oncology. He will present the results June 5 in a plenary session featuring the most important research at the meeting.

Acute lymphoblastic leukemia (ALL) is the most common leukemia in children. Children with high-risk ALL have a high white blood count at diagnosis and/or are 10 years or more of age.

Although pediatric ALL has a high cure rate and the standard regimen had reduced relapses in the bone marrow over time, investigators were concerned that relapses in the central nervous system had not declined as much. Therefore, they sought a regimen with the potential for greater penetration of tumor cells in the central nervous system.

When the study was conceived 10 years ago, the investigators did not have a new drug or targeted therapy, however, said Dr. Larsen, director of the Maine Children’s Cancer Program and the division of pediatric hematology/oncology at the Barbara Bush Children’s Hospital at Maine Medical Center in Portland. Therefore, "rather than trying something brand new," they decided to try to optimize treatment with a drug that "had been around for awhile."

One of the earliest chemotherapy drugs, methotrexate promotes cancer cell death by preventing leukemia cells from using folate, an essential vitamin. Its use dates to 1947 when Dr. Sidney Farber induced the first remissions in children with ALL by giving them an early form of methotrexate called aminopterin. It is an essential component of treatment for pediatric ALL, but the optimal regimen was not resolved.

Dr. Richard Schilsky, a professor of medicine and chief of the section of hematology-oncology at the University of Chicago Pritzker School of Medicine, suggested oncologists treating adults have much to learn from how the investigators focused on an existing therapy. "The pediatric oncologists have recognized that to get optimal results in treating cancer you have to optimize the way cancer treatment is given," said Dr. Schilsky, a former ASCO president and moderator of the press briefing.

The Children’s Oncology Group AALL0232 trial started in 2004 and enrolled 3,154 newly diagnosed patients ages 1 to 30. Most pediatric ALL trials do not enroll patients older than 21 years of age, Dr. Larsen said in an interview, but current thinking suggests that young adult patients may do better on pediatric protocols.

At the time of the interim analysis, 2,426 patients had been randomized. About half the population in the interim analysis, 1,217 patients, was treated with a standard Capizzi regimen in which intravenous methotrexate is delivered at a starting dose of 100 mg/m² and escalated by 50 mg/m² every 10 days up to a maximum of 5 doses depending on the child’s ability to tolerate the medication. In this regimen methotrexate is followed by a second chemotherapy drug called asparaginase.

The other 1,209 patients were assigned to the high-dose arm, and received 5 g/m² – that is, 5,000 mg/m² of methotrexate biweekly in four doses.

Despite concerns that the high-dose regimen would lead to more toxicity, febrile neutropenia occurred less in the experimental arm of the trial: 5.2% vs. 8.2% in the standard arm (P = .005). Leucovorin rescue was available for patients on high-dose methotrexate, which may partially explain the lower incidence of neutropenia in this group. Acute neurotoxicity, osteonecrosis, and other clinically relevant side effects were not significantly different.

Investigators are not sure why the high-dose regimen is less toxic, but side effects with standard therapy may be more the result of the combination of drugs in the Capizzi regimen than of methotrexate itself, Dr. Larsen said.

A substudy is looking at the comparative costs of the two regimens, he added. Methotrexate is inexpensive, but the high-dose regimen requires hospitalization. This needs to be balanced against the cost of hospitalizing and treating with antibiotics the greater proportion of children developing febrile neutropenia, a serious toxicity, on the Capizzi regimen.

A new wrinkle, Dr. Larsen noted, is that the Children’s Oncology Group and the adult Cancer and Leukemia Group B are planning a joint trial comparing adult and children’s regimens for teens and young adults with ALL. It was scheduled to use the Capizzi regimen but needs to be reconsidered.

The National Institutes of Health provided funds for the trial. Two co-authors said they received research funding from Becton-Dickinson.

CHICAGO — A new chemotherapy regimen that starts children and young adults on 50 times the standard dose of methotrexate for high-risk B-precursor acute lymphoblastic leukemia leads to significantly fewer recurrences five years after treatment without an increase in toxicity.

A randomized phase III trial comparing the high-dose regimen to standard therapy was halted in January 2011 after an interim analysis found the 5-year event-free survival rate reached 82% with the new regimen vs. 75% with the old (P = .0006).

Pediatric oncologists began using the new high-dose regimen as standard practice "as soon as we stopped the protocol," Dr. Eric C. Larsen, principal investigator of the study, said at a press briefing June 3, on the opening day of the annual meeting of the American Society of Clinical Oncology. He will present the results June 5 in a plenary session featuring the most important research at the meeting.

Acute lymphoblastic leukemia (ALL) is the most common leukemia in children. Children with high-risk ALL have a high white blood count at diagnosis and/or are 10 years or more of age.

Although pediatric ALL has a high cure rate and the standard regimen had reduced relapses in the bone marrow over time, investigators were concerned that relapses in the central nervous system had not declined as much. Therefore, they sought a regimen with the potential for greater penetration of tumor cells in the central nervous system.

When the study was conceived 10 years ago, the investigators did not have a new drug or targeted therapy, however, said Dr. Larsen, director of the Maine Children’s Cancer Program and the division of pediatric hematology/oncology at the Barbara Bush Children’s Hospital at Maine Medical Center in Portland. Therefore, "rather than trying something brand new," they decided to try to optimize treatment with a drug that "had been around for awhile."

One of the earliest chemotherapy drugs, methotrexate promotes cancer cell death by preventing leukemia cells from using folate, an essential vitamin. Its use dates to 1947 when Dr. Sidney Farber induced the first remissions in children with ALL by giving them an early form of methotrexate called aminopterin. It is an essential component of treatment for pediatric ALL, but the optimal regimen was not resolved.

Dr. Richard Schilsky, a professor of medicine and chief of the section of hematology-oncology at the University of Chicago Pritzker School of Medicine, suggested oncologists treating adults have much to learn from how the investigators focused on an existing therapy. "The pediatric oncologists have recognized that to get optimal results in treating cancer you have to optimize the way cancer treatment is given," said Dr. Schilsky, a former ASCO president and moderator of the press briefing.

The Children’s Oncology Group AALL0232 trial started in 2004 and enrolled 3,154 newly diagnosed patients ages 1 to 30. Most pediatric ALL trials do not enroll patients older than 21 years of age, Dr. Larsen said in an interview, but current thinking suggests that young adult patients may do better on pediatric protocols.

At the time of the interim analysis, 2,426 patients had been randomized. About half the population in the interim analysis, 1,217 patients, was treated with a standard Capizzi regimen in which intravenous methotrexate is delivered at a starting dose of 100 mg/m² and escalated by 50 mg/m² every 10 days up to a maximum of 5 doses depending on the child’s ability to tolerate the medication. In this regimen methotrexate is followed by a second chemotherapy drug called asparaginase.

The other 1,209 patients were assigned to the high-dose arm, and received 5 g/m² – that is, 5,000 mg/m² of methotrexate biweekly in four doses.

Despite concerns that the high-dose regimen would lead to more toxicity, febrile neutropenia occurred less in the experimental arm of the trial: 5.2% vs. 8.2% in the standard arm (P = .005). Leucovorin rescue was available for patients on high-dose methotrexate, which may partially explain the lower incidence of neutropenia in this group. Acute neurotoxicity, osteonecrosis, and other clinically relevant side effects were not significantly different.

Investigators are not sure why the high-dose regimen is less toxic, but side effects with standard therapy may be more the result of the combination of drugs in the Capizzi regimen than of methotrexate itself, Dr. Larsen said.

A substudy is looking at the comparative costs of the two regimens, he added. Methotrexate is inexpensive, but the high-dose regimen requires hospitalization. This needs to be balanced against the cost of hospitalizing and treating with antibiotics the greater proportion of children developing febrile neutropenia, a serious toxicity, on the Capizzi regimen.

A new wrinkle, Dr. Larsen noted, is that the Children’s Oncology Group and the adult Cancer and Leukemia Group B are planning a joint trial comparing adult and children’s regimens for teens and young adults with ALL. It was scheduled to use the Capizzi regimen but needs to be reconsidered.

The National Institutes of Health provided funds for the trial. Two co-authors said they received research funding from Becton-Dickinson.

CHICAGO — A new chemotherapy regimen that starts children and young adults on 50 times the standard dose of methotrexate for high-risk B-precursor acute lymphoblastic leukemia leads to significantly fewer recurrences five years after treatment without an increase in toxicity.

A randomized phase III trial comparing the high-dose regimen to standard therapy was halted in January 2011 after an interim analysis found the 5-year event-free survival rate reached 82% with the new regimen vs. 75% with the old (P = .0006).

Pediatric oncologists began using the new high-dose regimen as standard practice "as soon as we stopped the protocol," Dr. Eric C. Larsen, principal investigator of the study, said at a press briefing June 3, on the opening day of the annual meeting of the American Society of Clinical Oncology. He will present the results June 5 in a plenary session featuring the most important research at the meeting.

Acute lymphoblastic leukemia (ALL) is the most common leukemia in children. Children with high-risk ALL have a high white blood count at diagnosis and/or are 10 years or more of age.

Although pediatric ALL has a high cure rate and the standard regimen had reduced relapses in the bone marrow over time, investigators were concerned that relapses in the central nervous system had not declined as much. Therefore, they sought a regimen with the potential for greater penetration of tumor cells in the central nervous system.

When the study was conceived 10 years ago, the investigators did not have a new drug or targeted therapy, however, said Dr. Larsen, director of the Maine Children’s Cancer Program and the division of pediatric hematology/oncology at the Barbara Bush Children’s Hospital at Maine Medical Center in Portland. Therefore, "rather than trying something brand new," they decided to try to optimize treatment with a drug that "had been around for awhile."

One of the earliest chemotherapy drugs, methotrexate promotes cancer cell death by preventing leukemia cells from using folate, an essential vitamin. Its use dates to 1947 when Dr. Sidney Farber induced the first remissions in children with ALL by giving them an early form of methotrexate called aminopterin. It is an essential component of treatment for pediatric ALL, but the optimal regimen was not resolved.

Dr. Richard Schilsky, a professor of medicine and chief of the section of hematology-oncology at the University of Chicago Pritzker School of Medicine, suggested oncologists treating adults have much to learn from how the investigators focused on an existing therapy. "The pediatric oncologists have recognized that to get optimal results in treating cancer you have to optimize the way cancer treatment is given," said Dr. Schilsky, a former ASCO president and moderator of the press briefing.

The Children’s Oncology Group AALL0232 trial started in 2004 and enrolled 3,154 newly diagnosed patients ages 1 to 30. Most pediatric ALL trials do not enroll patients older than 21 years of age, Dr. Larsen said in an interview, but current thinking suggests that young adult patients may do better on pediatric protocols.

At the time of the interim analysis, 2,426 patients had been randomized. About half the population in the interim analysis, 1,217 patients, was treated with a standard Capizzi regimen in which intravenous methotrexate is delivered at a starting dose of 100 mg/m² and escalated by 50 mg/m² every 10 days up to a maximum of 5 doses depending on the child’s ability to tolerate the medication. In this regimen methotrexate is followed by a second chemotherapy drug called asparaginase.

The other 1,209 patients were assigned to the high-dose arm, and received 5 g/m² – that is, 5,000 mg/m² of methotrexate biweekly in four doses.

Despite concerns that the high-dose regimen would lead to more toxicity, febrile neutropenia occurred less in the experimental arm of the trial: 5.2% vs. 8.2% in the standard arm (P = .005). Leucovorin rescue was available for patients on high-dose methotrexate, which may partially explain the lower incidence of neutropenia in this group. Acute neurotoxicity, osteonecrosis, and other clinically relevant side effects were not significantly different.

Investigators are not sure why the high-dose regimen is less toxic, but side effects with standard therapy may be more the result of the combination of drugs in the Capizzi regimen than of methotrexate itself, Dr. Larsen said.

A substudy is looking at the comparative costs of the two regimens, he added. Methotrexate is inexpensive, but the high-dose regimen requires hospitalization. This needs to be balanced against the cost of hospitalizing and treating with antibiotics the greater proportion of children developing febrile neutropenia, a serious toxicity, on the Capizzi regimen.

A new wrinkle, Dr. Larsen noted, is that the Children’s Oncology Group and the adult Cancer and Leukemia Group B are planning a joint trial comparing adult and children’s regimens for teens and young adults with ALL. It was scheduled to use the Capizzi regimen but needs to be reconsidered.

The National Institutes of Health provided funds for the trial. Two co-authors said they received research funding from Becton-Dickinson.

In a remarkable expansion of options for men with advanced prostate cancer, on April 28 the Food and Drug Administration issued its fourth approval of a new treatment for use in late-stage disease.

Abiraterone acetate is indicated for treatment of metastatic castration-resistant prostate cancer in men who have already received chemotherapy with docetaxel (Taxotere). An androgen suppressant, abiraterone decreases production of testosterone by inhibiting a protein called CYP17A1.

The new oral drug will be marketed as Zytiga by Johnson & Johnson’s Centocor Ortho Biotech of Horsham, Pa. It is to be used daily in combination with the steroid prednisone in late-stage disease.

The FDA considered abiraterone under its priority review program and acted ahead of its June 20, 2010, regulatory goal date. Approval was widely anticipated, as the abiraterone-prednisone combination was shown to prolong life by about 4 months in a randomized, international, phase III trial that enrolled 1,195 men whose disease was progressing after one or two chemotherapy regimens, including one with docetaxel.

Median overall survival reached 14.8 months with a daily dosage of 1,000 mg of abiraterone plus 5 mg of twice-daily prednisone vs. 10.9 months among late-stage patients who received a placebo with prednisone in the study. Investigators reported a 35% reduction in the risk of death (hazard ratio.646; P less than .0001).

Although more than half of patients had grade 3/4 toxicities, Dr. Johann de Bono of the Royal Marsden NHS Foundation Trust and the U.K. Institute of Cancer Research, both in London, described the drug as well tolerated when he presented the data in fall 2010 at the annual congress of the European Society for Medical Oncology.

The most commonly reported side effects, as listed by the FDA, included: "joint swelling or discomfort, low levels of potassium in the blood, fluid retention (usually of the legs and feet), muscle discomfort, hot flashes, diarrhea, urinary tract infection, cough, high blood pressure, heartbeat disorders, urinary frequency, increased nighttime urination, upset stomach or indigestion and upper respiratory tract infection."

The company announcement says abiraterone should be used with caution in patients who have a history of cardiovascular disease or "medical conditions that might be compromised by increases in hypertension, hypokalemia and fluid retention." It also recommends monitoring for adrenocortical insufficiency and hepatotoxicity, and advises that abiraterone should be taken on an empty stomach.

Abiraterone becomes the fourth drug approved for treatment of patients with prostate cancer over the last year. In April 2010, the agency approved the sipuleucel-T (Provenge) vaccine for asymptomatic or minimally symptomatic castration-resistant prostate cancer. This was followed in June 2010, by approval of cabazitaxel (Jevtana), a new injectable taxane that acts as a microtubule inhibitor, for use in combination with prednisone after the failure of a docetaxel-containing therapy.

Then, in November 2010 denosumab (Xgeva) received FDA approval for treatment of skeletal-related events in solid tumors. The indication was based in part on favorable results in a trial that enrolled 1,901 patients with hormone-refractory prostate cancer.

"The last 12 months have been unprecedented in the field of prostate cancer. Between April of 2010 and April of 2011, our field has seen four new therapeutic agents," commented Dr. Judd W. Moul, the James H. Semans, M.D. Professor of Surgery and chief of the Division of Urologic Surgery at Duke University Medical Center in Durham, N.C., in an interview.

"Our toolbox of therapeutic options has grown tremendously in the last year, and it is now more imperative than ever to embrace the multidisciplinary care team of urologists, medical oncologists, radiation oncologists, and other team members to best sequence and strategize for use of these new agents," he added.

Dr. de Bono is employed by the U.K. Institute of Cancer Research, London, which has a commercial interest in the development of abiraterone acetate and has served as a paid consultant of Johnson & Johnson.

In a remarkable expansion of options for men with advanced prostate cancer, on April 28 the Food and Drug Administration issued its fourth approval of a new treatment for use in late-stage disease.

Abiraterone acetate is indicated for treatment of metastatic castration-resistant prostate cancer in men who have already received chemotherapy with docetaxel (Taxotere). An androgen suppressant, abiraterone decreases production of testosterone by inhibiting a protein called CYP17A1.

The new oral drug will be marketed as Zytiga by Johnson & Johnson’s Centocor Ortho Biotech of Horsham, Pa. It is to be used daily in combination with the steroid prednisone in late-stage disease.

The FDA considered abiraterone under its priority review program and acted ahead of its June 20, 2010, regulatory goal date. Approval was widely anticipated, as the abiraterone-prednisone combination was shown to prolong life by about 4 months in a randomized, international, phase III trial that enrolled 1,195 men whose disease was progressing after one or two chemotherapy regimens, including one with docetaxel.

Median overall survival reached 14.8 months with a daily dosage of 1,000 mg of abiraterone plus 5 mg of twice-daily prednisone vs. 10.9 months among late-stage patients who received a placebo with prednisone in the study. Investigators reported a 35% reduction in the risk of death (hazard ratio.646; P less than .0001).

Although more than half of patients had grade 3/4 toxicities, Dr. Johann de Bono of the Royal Marsden NHS Foundation Trust and the U.K. Institute of Cancer Research, both in London, described the drug as well tolerated when he presented the data in fall 2010 at the annual congress of the European Society for Medical Oncology.

The most commonly reported side effects, as listed by the FDA, included: "joint swelling or discomfort, low levels of potassium in the blood, fluid retention (usually of the legs and feet), muscle discomfort, hot flashes, diarrhea, urinary tract infection, cough, high blood pressure, heartbeat disorders, urinary frequency, increased nighttime urination, upset stomach or indigestion and upper respiratory tract infection."

The company announcement says abiraterone should be used with caution in patients who have a history of cardiovascular disease or "medical conditions that might be compromised by increases in hypertension, hypokalemia and fluid retention." It also recommends monitoring for adrenocortical insufficiency and hepatotoxicity, and advises that abiraterone should be taken on an empty stomach.

Abiraterone becomes the fourth drug approved for treatment of patients with prostate cancer over the last year. In April 2010, the agency approved the sipuleucel-T (Provenge) vaccine for asymptomatic or minimally symptomatic castration-resistant prostate cancer. This was followed in June 2010, by approval of cabazitaxel (Jevtana), a new injectable taxane that acts as a microtubule inhibitor, for use in combination with prednisone after the failure of a docetaxel-containing therapy.

Then, in November 2010 denosumab (Xgeva) received FDA approval for treatment of skeletal-related events in solid tumors. The indication was based in part on favorable results in a trial that enrolled 1,901 patients with hormone-refractory prostate cancer.

"The last 12 months have been unprecedented in the field of prostate cancer. Between April of 2010 and April of 2011, our field has seen four new therapeutic agents," commented Dr. Judd W. Moul, the James H. Semans, M.D. Professor of Surgery and chief of the Division of Urologic Surgery at Duke University Medical Center in Durham, N.C., in an interview.

"Our toolbox of therapeutic options has grown tremendously in the last year, and it is now more imperative than ever to embrace the multidisciplinary care team of urologists, medical oncologists, radiation oncologists, and other team members to best sequence and strategize for use of these new agents," he added.

Dr. de Bono is employed by the U.K. Institute of Cancer Research, London, which has a commercial interest in the development of abiraterone acetate and has served as a paid consultant of Johnson & Johnson.

In a remarkable expansion of options for men with advanced prostate cancer, on April 28 the Food and Drug Administration issued its fourth approval of a new treatment for use in late-stage disease.

Abiraterone acetate is indicated for treatment of metastatic castration-resistant prostate cancer in men who have already received chemotherapy with docetaxel (Taxotere). An androgen suppressant, abiraterone decreases production of testosterone by inhibiting a protein called CYP17A1.

The new oral drug will be marketed as Zytiga by Johnson & Johnson’s Centocor Ortho Biotech of Horsham, Pa. It is to be used daily in combination with the steroid prednisone in late-stage disease.

The FDA considered abiraterone under its priority review program and acted ahead of its June 20, 2010, regulatory goal date. Approval was widely anticipated, as the abiraterone-prednisone combination was shown to prolong life by about 4 months in a randomized, international, phase III trial that enrolled 1,195 men whose disease was progressing after one or two chemotherapy regimens, including one with docetaxel.

Median overall survival reached 14.8 months with a daily dosage of 1,000 mg of abiraterone plus 5 mg of twice-daily prednisone vs. 10.9 months among late-stage patients who received a placebo with prednisone in the study. Investigators reported a 35% reduction in the risk of death (hazard ratio.646; P less than .0001).

Although more than half of patients had grade 3/4 toxicities, Dr. Johann de Bono of the Royal Marsden NHS Foundation Trust and the U.K. Institute of Cancer Research, both in London, described the drug as well tolerated when he presented the data in fall 2010 at the annual congress of the European Society for Medical Oncology.

The most commonly reported side effects, as listed by the FDA, included: "joint swelling or discomfort, low levels of potassium in the blood, fluid retention (usually of the legs and feet), muscle discomfort, hot flashes, diarrhea, urinary tract infection, cough, high blood pressure, heartbeat disorders, urinary frequency, increased nighttime urination, upset stomach or indigestion and upper respiratory tract infection."

The company announcement says abiraterone should be used with caution in patients who have a history of cardiovascular disease or "medical conditions that might be compromised by increases in hypertension, hypokalemia and fluid retention." It also recommends monitoring for adrenocortical insufficiency and hepatotoxicity, and advises that abiraterone should be taken on an empty stomach.

Abiraterone becomes the fourth drug approved for treatment of patients with prostate cancer over the last year. In April 2010, the agency approved the sipuleucel-T (Provenge) vaccine for asymptomatic or minimally symptomatic castration-resistant prostate cancer. This was followed in June 2010, by approval of cabazitaxel (Jevtana), a new injectable taxane that acts as a microtubule inhibitor, for use in combination with prednisone after the failure of a docetaxel-containing therapy.

Then, in November 2010 denosumab (Xgeva) received FDA approval for treatment of skeletal-related events in solid tumors. The indication was based in part on favorable results in a trial that enrolled 1,901 patients with hormone-refractory prostate cancer.

"The last 12 months have been unprecedented in the field of prostate cancer. Between April of 2010 and April of 2011, our field has seen four new therapeutic agents," commented Dr. Judd W. Moul, the James H. Semans, M.D. Professor of Surgery and chief of the Division of Urologic Surgery at Duke University Medical Center in Durham, N.C., in an interview.

"Our toolbox of therapeutic options has grown tremendously in the last year, and it is now more imperative than ever to embrace the multidisciplinary care team of urologists, medical oncologists, radiation oncologists, and other team members to best sequence and strategize for use of these new agents," he added.

Dr. de Bono is employed by the U.K. Institute of Cancer Research, London, which has a commercial interest in the development of abiraterone acetate and has served as a paid consultant of Johnson & Johnson.

In a remarkable expansion of options for men with advanced prostate cancer, on April 28 the Food and Drug Administration issued its fourth approval of a new treatment for use in late-stage disease.

Abiraterone acetate is indicated for treatment of metastatic castration-resistant prostate cancer in men who have already received chemotherapy with docetaxel (Taxotere). An androgen suppressant, abiraterone decreases production of testosterone by inhibiting a protein called CYP17A1.

The new oral drug will be marketed as Zytiga by Johnson & Johnson’s Centocor Ortho Biotech of Horsham, Pa. It is to be used daily in combination with the steroid prednisone in late-stage disease.

The FDA considered abiraterone under its priority review program and acted ahead of its June 20, 2010, regulatory goal date. Approval was widely anticipated, as the abiraterone-prednisone combination was shown to prolong life by about 4 months in a randomized, international, phase III trial that enrolled 1,195 men whose disease was progressing after one or two chemotherapy regimens, including one with docetaxel.

Median overall survival reached 14.8 months with a daily dosage of 1,000 mg of abiraterone plus 5 mg of twice-daily prednisone vs. 10.9 months among late-stage patients who received a placebo with prednisone in the study. Investigators reported a 35% reduction in the risk of death (hazard ratio.646; P less than .0001).

Although more than half of patients had grade 3/4 toxicities, Dr. Johann de Bono of the Royal Marsden NHS Foundation Trust and the U.K. Institute of Cancer Research, both in London, described the drug as well tolerated when he presented the data in fall 2010 at the annual congress of the European Society for Medical Oncology.

The most commonly reported side effects, as listed by the FDA, included: "joint swelling or discomfort, low levels of potassium in the blood, fluid retention (usually of the legs and feet), muscle discomfort, hot flashes, diarrhea, urinary tract infection, cough, high blood pressure, heartbeat disorders, urinary frequency, increased nighttime urination, upset stomach or indigestion and upper respiratory tract infection."

The company announcement says abiraterone should be used with caution in patients who have a history of cardiovascular disease or "medical conditions that might be compromised by increases in hypertension, hypokalemia and fluid retention." It also recommends monitoring for adrenocortical insufficiency and hepatotoxicity, and advises that abiraterone should be taken on an empty stomach.

Abiraterone becomes the fourth drug approved for treatment of patients with prostate cancer over the last year. In April 2010, the agency approved the sipuleucel-T (Provenge) vaccine for asymptomatic or minimally symptomatic castration-resistant prostate cancer. This was followed in June 2010, by approval of cabazitaxel (Jevtana), a new injectable taxane that acts as a microtubule inhibitor, for use in combination with prednisone after the failure of a docetaxel-containing therapy.

Then, in November 2010 denosumab (Xgeva) received FDA approval for treatment of skeletal-related events in solid tumors. The indication was based in part on favorable results in a trial that enrolled 1,901 patients with hormone-refractory prostate cancer.

"The last 12 months have been unprecedented in the field of prostate cancer. Between April of 2010 and April of 2011, our field has seen four new therapeutic agents," commented Dr. Judd W. Moul, the James H. Semans, M.D. Professor of Surgery and chief of the Division of Urologic Surgery at Duke University Medical Center in Durham, N.C., in an interview.

"Our toolbox of therapeutic options has grown tremendously in the last year, and it is now more imperative than ever to embrace the multidisciplinary care team of urologists, medical oncologists, radiation oncologists, and other team members to best sequence and strategize for use of these new agents," he added.

Dr. de Bono is employed by the U.K. Institute of Cancer Research, London, which has a commercial interest in the development of abiraterone acetate and has served as a paid consultant of Johnson & Johnson.

In a remarkable expansion of options for men with advanced prostate cancer, on April 28 the Food and Drug Administration issued its fourth approval of a new treatment for use in late-stage disease.

Abiraterone acetate is indicated for treatment of metastatic castration-resistant prostate cancer in men who have already received chemotherapy with docetaxel (Taxotere). An androgen suppressant, abiraterone decreases production of testosterone by inhibiting a protein called CYP17A1.

The new oral drug will be marketed as Zytiga by Johnson & Johnson’s Centocor Ortho Biotech of Horsham, Pa. It is to be used daily in combination with the steroid prednisone in late-stage disease.

The FDA considered abiraterone under its priority review program and acted ahead of its June 20, 2010, regulatory goal date. Approval was widely anticipated, as the abiraterone-prednisone combination was shown to prolong life by about 4 months in a randomized, international, phase III trial that enrolled 1,195 men whose disease was progressing after one or two chemotherapy regimens, including one with docetaxel.

Median overall survival reached 14.8 months with a daily dosage of 1,000 mg of abiraterone plus 5 mg of twice-daily prednisone vs. 10.9 months among late-stage patients who received a placebo with prednisone in the study. Investigators reported a 35% reduction in the risk of death (hazard ratio.646; P less than .0001).

Although more than half of patients had grade 3/4 toxicities, Dr. Johann de Bono of the Royal Marsden NHS Foundation Trust and the U.K. Institute of Cancer Research, both in London, described the drug as well tolerated when he presented the data in fall 2010 at the annual congress of the European Society for Medical Oncology.

The most commonly reported side effects, as listed by the FDA, included: "joint swelling or discomfort, low levels of potassium in the blood, fluid retention (usually of the legs and feet), muscle discomfort, hot flashes, diarrhea, urinary tract infection, cough, high blood pressure, heartbeat disorders, urinary frequency, increased nighttime urination, upset stomach or indigestion and upper respiratory tract infection."

The company announcement says abiraterone should be used with caution in patients who have a history of cardiovascular disease or "medical conditions that might be compromised by increases in hypertension, hypokalemia and fluid retention." It also recommends monitoring for adrenocortical insufficiency and hepatotoxicity, and advises that abiraterone should be taken on an empty stomach.

Abiraterone becomes the fourth drug approved for treatment of patients with prostate cancer over the last year. In April 2010, the agency approved the sipuleucel-T (Provenge) vaccine for asymptomatic or minimally symptomatic castration-resistant prostate cancer. This was followed in June 2010, by approval of cabazitaxel (Jevtana), a new injectable taxane that acts as a microtubule inhibitor, for use in combination with prednisone after the failure of a docetaxel-containing therapy.

Then, in November 2010 denosumab (Xgeva) received FDA approval for treatment of skeletal-related events in solid tumors. The indication was based in part on favorable results in a trial that enrolled 1,901 patients with hormone-refractory prostate cancer.

"The last 12 months have been unprecedented in the field of prostate cancer. Between April of 2010 and April of 2011, our field has seen four new therapeutic agents," commented Dr. Judd W. Moul, the James H. Semans, M.D. Professor of Surgery and chief of the Division of Urologic Surgery at Duke University Medical Center in Durham, N.C., in an interview.

"Our toolbox of therapeutic options has grown tremendously in the last year, and it is now more imperative than ever to embrace the multidisciplinary care team of urologists, medical oncologists, radiation oncologists, and other team members to best sequence and strategize for use of these new agents," he added.

Dr. de Bono is employed by the U.K. Institute of Cancer Research, London, which has a commercial interest in the development of abiraterone acetate and has served as a paid consultant of Johnson & Johnson.

In a remarkable expansion of options for men with advanced prostate cancer, on April 28 the Food and Drug Administration issued its fourth approval of a new treatment for use in late-stage disease.

Abiraterone acetate is indicated for treatment of metastatic castration-resistant prostate cancer in men who have already received chemotherapy with docetaxel (Taxotere). An androgen suppressant, abiraterone decreases production of testosterone by inhibiting a protein called CYP17A1.

The new oral drug will be marketed as Zytiga by Johnson & Johnson’s Centocor Ortho Biotech of Horsham, Pa. It is to be used daily in combination with the steroid prednisone in late-stage disease.

The FDA considered abiraterone under its priority review program and acted ahead of its June 20, 2010, regulatory goal date. Approval was widely anticipated, as the abiraterone-prednisone combination was shown to prolong life by about 4 months in a randomized, international, phase III trial that enrolled 1,195 men whose disease was progressing after one or two chemotherapy regimens, including one with docetaxel.

Median overall survival reached 14.8 months with a daily dosage of 1,000 mg of abiraterone plus 5 mg of twice-daily prednisone vs. 10.9 months among late-stage patients who received a placebo with prednisone in the study. Investigators reported a 35% reduction in the risk of death (hazard ratio.646; P less than .0001).

Although more than half of patients had grade 3/4 toxicities, Dr. Johann de Bono of the Royal Marsden NHS Foundation Trust and the U.K. Institute of Cancer Research, both in London, described the drug as well tolerated when he presented the data in fall 2010 at the annual congress of the European Society for Medical Oncology.

The most commonly reported side effects, as listed by the FDA, included: "joint swelling or discomfort, low levels of potassium in the blood, fluid retention (usually of the legs and feet), muscle discomfort, hot flashes, diarrhea, urinary tract infection, cough, high blood pressure, heartbeat disorders, urinary frequency, increased nighttime urination, upset stomach or indigestion and upper respiratory tract infection."

The company announcement says abiraterone should be used with caution in patients who have a history of cardiovascular disease or "medical conditions that might be compromised by increases in hypertension, hypokalemia and fluid retention." It also recommends monitoring for adrenocortical insufficiency and hepatotoxicity, and advises that abiraterone should be taken on an empty stomach.

Abiraterone becomes the fourth drug approved for treatment of patients with prostate cancer over the last year. In April 2010, the agency approved the sipuleucel-T (Provenge) vaccine for asymptomatic or minimally symptomatic castration-resistant prostate cancer. This was followed in June 2010, by approval of cabazitaxel (Jevtana), a new injectable taxane that acts as a microtubule inhibitor, for use in combination with prednisone after the failure of a docetaxel-containing therapy.

Then, in November 2010 denosumab (Xgeva) received FDA approval for treatment of skeletal-related events in solid tumors. The indication was based in part on favorable results in a trial that enrolled 1,901 patients with hormone-refractory prostate cancer.

"The last 12 months have been unprecedented in the field of prostate cancer. Between April of 2010 and April of 2011, our field has seen four new therapeutic agents," commented Dr. Judd W. Moul, the James H. Semans, M.D. Professor of Surgery and chief of the Division of Urologic Surgery at Duke University Medical Center in Durham, N.C., in an interview.

"Our toolbox of therapeutic options has grown tremendously in the last year, and it is now more imperative than ever to embrace the multidisciplinary care team of urologists, medical oncologists, radiation oncologists, and other team members to best sequence and strategize for use of these new agents," he added.

Dr. de Bono is employed by the U.K. Institute of Cancer Research, London, which has a commercial interest in the development of abiraterone acetate and has served as a paid consultant of Johnson & Johnson.