Prostate Cancer Therapies: From Fast-Track to Graveyard-Bound

CHICAGO – Updated and final analyses from four phase III prostate cancer trials offer continued support for radium-223, insights into denosumab and multimodal therapy, and an obituary for yet another drug in castration-resistant prostate cancer.

Radium-223 Boosts Overall Survival

Updated results from the phase III ALSYMPCA trial show that radium-223 chloride (Alpharadin) increased median overall survival by 3.6 months, from 11.3 months to 14.9 months (hazard ratio, 0.695; P = .00007), resulting in a 30.5% reduction in the risk of death, compared with placebo, in men with castration-resistant prostate cancer (CRPC) and bone metastases.

The experimental alpha-emitting particle also significantly prolonged the time to first skeletal-related event, from 6.7 months to 12.2 months (HR, 0.64; P less than .0001), said Dr. Chris Parker of the Royal Marsden Hospital, London, at the annual meeting of the American Society of Clinical Oncology.

The updated results surpass the overall survival benefit reported for radium-223 chloride in an interim analysis at the 2011 European Multidisciplinary Cancer Congress.

The Food and Drug Administration very quickly granted fast-track designation to radium-223 chloride, and earlier this year agreed that Bayer HealthCare could make the drug available to patients who had CRPC or hormone-refractory prostate cancer with symptomatic bone metastases at qualified clinical sites through its expanded-access program.

Based on the ALSYMPCA data, Bayer is expected to file radium-223 chloride for CRPC with regulatory authorities in the second half of 2012, and is planning trials in earlier-stage disease and other cancers. Recruitment is already underway for a trial of radium-223 in combination with docetaxel (Taxotere) in patients with bone metastasis from CRPC.

Denosumab Data Did Not Sway FDA

The shorter the prostate-specific antigen doubling time (PSADT), the greater the impact is of denosumab (Xgeva) in nonmetastatic CRPC, according to an exploratory, post hoc subset analysis of the denosumab 147 trial.

If the PSADT was 6 months or less, denosumab increased median bone metastasis-free survival by 7.2 months to 25.9 months, from a median of 18.7 months with placebo (HR, 0.77; P = .006), which translates into a 23% risk reduction.

If the PSADT was less than 4 months, the delay increased by 7.5 months, from a median of 18.3 months with placebo to 25.8 months with denosumab (HR, 0.71; P = .004), corresponding to a 29% risk reduction, reported Dr. Fred Saad, professor and chief of urology at the University of Montreal Hospital Centre.

Discussant Dr. Eric Small, codirector of urologic oncology at the University of California, San Francisco, said that the study validates PSADT as an important risk stratifier in this group of patients, but observed that denosumab is not approved for this indication, and it appears to have the greatest benefit in a diminishingly small group of patients with shorter and shorter PSA doubling times.

"This is wonderful hypothesis generation, but cannot be used for the basis of therapeutic decisions," he said.

Bone metastasis–free survival in the entire cohort was 25.2 months with placebo and 29.5 months with denosumab (HR, 0.85; P = .028).

In February, an FDA advisory panel voted that denosumab does not have a favorable risk-benefit profile as a treatment to reduce the risk of bone metastasis in high-risk men (defined as those with a PSA level of at least 8.0 ng/mL or a PSA that doubled within 10 months or less).

Multimodal Benefit Goes 10 Years

The survival benefit of adding radiotherapy (RT) to androgen deprivation therapy (ADT) was maintained at 10 years in men with locally advanced prostate cancer, according to the final analysis of a phase III intergroup trial carried out by the U.K. Medical Research Council, the National Cancer Institute of Canada, and the Southwest Oncology Group.

At 10 years, 55% of men who were treated with ADT plus RT were alive, compared with 49% given ADT alone (HR, 0.70; P = .0003). The difference in disease-specific survival was particularly striking at 15% vs. 26%, favoring the combination (HR, 0.46; P less than .0001).

"That’s more than halving the risk of death from prostate cancer," said Prof. Malcolm D. Mason, head of oncology and palliative medicine at Cardiff (Wales) University.

In an interim analysis reported at ASCO 2010, RT plus ADT provided significant improvements at 7 years in overall survival (HR, 0.77; P = .033) and disease-specific survival (DSS; HR, 0.54; P = .0001).

In the current analysis, bowel and urinary morbidity were transiently elevated with the addition of radiation, most often delivered at a dose of 65-69 Gy, but were no different after 3 years.

An exploratory analysis favored whole pelvic vs. prostate-only radiation for overall survival (HR, 0.90; P = .57) and DSS (HR, 0.65; P = .15), but Dr. Mason called this finding hypothesis generating.

He remarked that combined ADT plus RT is enshrined in the European Association of Urology and National Comprehensive Cancer Network guidelines, "but that uptake is uncertain, and we have concerns as to whether this has been taken up as much as it should have been."

Dr. Small agreed with the authors’ conclusion that ADT and RT should be offered to all men with locally advanced prostate cancer suitable for RT, but said the absolute difference in 10-year overall-survival is modest, at 6%. Because accrual took place 10 years ago, the results also cannot be fully extrapolated to the increasingly common high-risk patients seen in the United States, who tend to be at a high grade and lower stage.

He pointed out that the combination arm had a 5% absolute increase in deaths because of secondary malignancies, which warrants exploration. "It makes you wonder what the radiation is doing here," he added.

Still, Dr. Small commended the authors for persevering with what he described as a tough study to do with a nonradiation arm. "This study is a demonstration of the power of the cooperative groups, and in an era of shrinking resources, points out that undersourcing the cooperative groups – as has been advocated by some – is shortsighted," he said.

Atrasentan Flops Again

Dr. David I. Quinn had the unenviable task of delivering the final word on atrasentan (Xinlay) as a prostate cancer therapy. The selective endothelin blocker failed as monotherapy in two previous phase III trials, and was so ineffective in combination with docetaxel that the phase III Southwest Oncology Group S0421 trial in advanced castration-resistant disease was halted early last year.

A new post hoc analysis from S0421 identified an 8-month survival benefit with atrasentan in a distinct subset of poor-prognosis patients with skeletal metastases and four bone metabolism biomarkers (median, 13 months vs. 5 months; P = .02).

Still, the drug proved futile when compared with docetaxel plus placebo in the entire cohort for time to progression (median, 9 months for both; HR, 1.03; P = .71) and overall survival (median, 18 months for both; HR, 1.04; P = .61). The 2-year progression-free survival was 18% in both groups, and overall survival rates were 37% and 38%, respectively.

"Endothelin blockade with currently available drugs such as atrasentan and zibotentan, which has three negative studies, is now a failed experiment," said Dr. Quinn, coleader of genitourinary medical oncology at the University of Southern California, Los Angeles. "It has been superseded by osteoblast-targeted therapy that actually works, like radium-223."

Dr. Parker reported consulting or advising for Algeta and receiving honoraria from Bayer; his coauthors reported financial relationships including employment with Algeta, which initiated the ALSYMPCA trial. Dr. Saad reported consulting or advising for and receiving honorarium and research funding from Amgen. Dr. Mason reported no disclosures. Dr. Quinn reported financial relationships with several firms. SWOG S0421 was supported by the Eastern Cooperative Oncology Group and Cancer and Leukemia Group B. Dr. Small reported consulting or advising for Dendreon and receiving research funding from Genzyme and Sanofi.

CHICAGO – Updated and final analyses from four phase III prostate cancer trials offer continued support for radium-223, insights into denosumab and multimodal therapy, and an obituary for yet another drug in castration-resistant prostate cancer.

Radium-223 Boosts Overall Survival

Updated results from the phase III ALSYMPCA trial show that radium-223 chloride (Alpharadin) increased median overall survival by 3.6 months, from 11.3 months to 14.9 months (hazard ratio, 0.695; P = .00007), resulting in a 30.5% reduction in the risk of death, compared with placebo, in men with castration-resistant prostate cancer (CRPC) and bone metastases.

The experimental alpha-emitting particle also significantly prolonged the time to first skeletal-related event, from 6.7 months to 12.2 months (HR, 0.64; P less than .0001), said Dr. Chris Parker of the Royal Marsden Hospital, London, at the annual meeting of the American Society of Clinical Oncology.

The updated results surpass the overall survival benefit reported for radium-223 chloride in an interim analysis at the 2011 European Multidisciplinary Cancer Congress.

The Food and Drug Administration very quickly granted fast-track designation to radium-223 chloride, and earlier this year agreed that Bayer HealthCare could make the drug available to patients who had CRPC or hormone-refractory prostate cancer with symptomatic bone metastases at qualified clinical sites through its expanded-access program.

Based on the ALSYMPCA data, Bayer is expected to file radium-223 chloride for CRPC with regulatory authorities in the second half of 2012, and is planning trials in earlier-stage disease and other cancers. Recruitment is already underway for a trial of radium-223 in combination with docetaxel (Taxotere) in patients with bone metastasis from CRPC.

Denosumab Data Did Not Sway FDA

The shorter the prostate-specific antigen doubling time (PSADT), the greater the impact is of denosumab (Xgeva) in nonmetastatic CRPC, according to an exploratory, post hoc subset analysis of the denosumab 147 trial.

If the PSADT was 6 months or less, denosumab increased median bone metastasis-free survival by 7.2 months to 25.9 months, from a median of 18.7 months with placebo (HR, 0.77; P = .006), which translates into a 23% risk reduction.

If the PSADT was less than 4 months, the delay increased by 7.5 months, from a median of 18.3 months with placebo to 25.8 months with denosumab (HR, 0.71; P = .004), corresponding to a 29% risk reduction, reported Dr. Fred Saad, professor and chief of urology at the University of Montreal Hospital Centre.

Discussant Dr. Eric Small, codirector of urologic oncology at the University of California, San Francisco, said that the study validates PSADT as an important risk stratifier in this group of patients, but observed that denosumab is not approved for this indication, and it appears to have the greatest benefit in a diminishingly small group of patients with shorter and shorter PSA doubling times.

"This is wonderful hypothesis generation, but cannot be used for the basis of therapeutic decisions," he said.

Bone metastasis–free survival in the entire cohort was 25.2 months with placebo and 29.5 months with denosumab (HR, 0.85; P = .028).

In February, an FDA advisory panel voted that denosumab does not have a favorable risk-benefit profile as a treatment to reduce the risk of bone metastasis in high-risk men (defined as those with a PSA level of at least 8.0 ng/mL or a PSA that doubled within 10 months or less).

Multimodal Benefit Goes 10 Years

The survival benefit of adding radiotherapy (RT) to androgen deprivation therapy (ADT) was maintained at 10 years in men with locally advanced prostate cancer, according to the final analysis of a phase III intergroup trial carried out by the U.K. Medical Research Council, the National Cancer Institute of Canada, and the Southwest Oncology Group.

At 10 years, 55% of men who were treated with ADT plus RT were alive, compared with 49% given ADT alone (HR, 0.70; P = .0003). The difference in disease-specific survival was particularly striking at 15% vs. 26%, favoring the combination (HR, 0.46; P less than .0001).

"That’s more than halving the risk of death from prostate cancer," said Prof. Malcolm D. Mason, head of oncology and palliative medicine at Cardiff (Wales) University.

In an interim analysis reported at ASCO 2010, RT plus ADT provided significant improvements at 7 years in overall survival (HR, 0.77; P = .033) and disease-specific survival (DSS; HR, 0.54; P = .0001).

In the current analysis, bowel and urinary morbidity were transiently elevated with the addition of radiation, most often delivered at a dose of 65-69 Gy, but were no different after 3 years.

An exploratory analysis favored whole pelvic vs. prostate-only radiation for overall survival (HR, 0.90; P = .57) and DSS (HR, 0.65; P = .15), but Dr. Mason called this finding hypothesis generating.

He remarked that combined ADT plus RT is enshrined in the European Association of Urology and National Comprehensive Cancer Network guidelines, "but that uptake is uncertain, and we have concerns as to whether this has been taken up as much as it should have been."

Dr. Small agreed with the authors’ conclusion that ADT and RT should be offered to all men with locally advanced prostate cancer suitable for RT, but said the absolute difference in 10-year overall-survival is modest, at 6%. Because accrual took place 10 years ago, the results also cannot be fully extrapolated to the increasingly common high-risk patients seen in the United States, who tend to be at a high grade and lower stage.

He pointed out that the combination arm had a 5% absolute increase in deaths because of secondary malignancies, which warrants exploration. "It makes you wonder what the radiation is doing here," he added.

Still, Dr. Small commended the authors for persevering with what he described as a tough study to do with a nonradiation arm. "This study is a demonstration of the power of the cooperative groups, and in an era of shrinking resources, points out that undersourcing the cooperative groups – as has been advocated by some – is shortsighted," he said.

Atrasentan Flops Again

Dr. David I. Quinn had the unenviable task of delivering the final word on atrasentan (Xinlay) as a prostate cancer therapy. The selective endothelin blocker failed as monotherapy in two previous phase III trials, and was so ineffective in combination with docetaxel that the phase III Southwest Oncology Group S0421 trial in advanced castration-resistant disease was halted early last year.

A new post hoc analysis from S0421 identified an 8-month survival benefit with atrasentan in a distinct subset of poor-prognosis patients with skeletal metastases and four bone metabolism biomarkers (median, 13 months vs. 5 months; P = .02).

Still, the drug proved futile when compared with docetaxel plus placebo in the entire cohort for time to progression (median, 9 months for both; HR, 1.03; P = .71) and overall survival (median, 18 months for both; HR, 1.04; P = .61). The 2-year progression-free survival was 18% in both groups, and overall survival rates were 37% and 38%, respectively.

"Endothelin blockade with currently available drugs such as atrasentan and zibotentan, which has three negative studies, is now a failed experiment," said Dr. Quinn, coleader of genitourinary medical oncology at the University of Southern California, Los Angeles. "It has been superseded by osteoblast-targeted therapy that actually works, like radium-223."

Dr. Parker reported consulting or advising for Algeta and receiving honoraria from Bayer; his coauthors reported financial relationships including employment with Algeta, which initiated the ALSYMPCA trial. Dr. Saad reported consulting or advising for and receiving honorarium and research funding from Amgen. Dr. Mason reported no disclosures. Dr. Quinn reported financial relationships with several firms. SWOG S0421 was supported by the Eastern Cooperative Oncology Group and Cancer and Leukemia Group B. Dr. Small reported consulting or advising for Dendreon and receiving research funding from Genzyme and Sanofi.

CHICAGO – Updated and final analyses from four phase III prostate cancer trials offer continued support for radium-223, insights into denosumab and multimodal therapy, and an obituary for yet another drug in castration-resistant prostate cancer.

Radium-223 Boosts Overall Survival

Updated results from the phase III ALSYMPCA trial show that radium-223 chloride (Alpharadin) increased median overall survival by 3.6 months, from 11.3 months to 14.9 months (hazard ratio, 0.695; P = .00007), resulting in a 30.5% reduction in the risk of death, compared with placebo, in men with castration-resistant prostate cancer (CRPC) and bone metastases.

The experimental alpha-emitting particle also significantly prolonged the time to first skeletal-related event, from 6.7 months to 12.2 months (HR, 0.64; P less than .0001), said Dr. Chris Parker of the Royal Marsden Hospital, London, at the annual meeting of the American Society of Clinical Oncology.

The updated results surpass the overall survival benefit reported for radium-223 chloride in an interim analysis at the 2011 European Multidisciplinary Cancer Congress.

The Food and Drug Administration very quickly granted fast-track designation to radium-223 chloride, and earlier this year agreed that Bayer HealthCare could make the drug available to patients who had CRPC or hormone-refractory prostate cancer with symptomatic bone metastases at qualified clinical sites through its expanded-access program.

Based on the ALSYMPCA data, Bayer is expected to file radium-223 chloride for CRPC with regulatory authorities in the second half of 2012, and is planning trials in earlier-stage disease and other cancers. Recruitment is already underway for a trial of radium-223 in combination with docetaxel (Taxotere) in patients with bone metastasis from CRPC.

Denosumab Data Did Not Sway FDA

The shorter the prostate-specific antigen doubling time (PSADT), the greater the impact is of denosumab (Xgeva) in nonmetastatic CRPC, according to an exploratory, post hoc subset analysis of the denosumab 147 trial.

If the PSADT was 6 months or less, denosumab increased median bone metastasis-free survival by 7.2 months to 25.9 months, from a median of 18.7 months with placebo (HR, 0.77; P = .006), which translates into a 23% risk reduction.

If the PSADT was less than 4 months, the delay increased by 7.5 months, from a median of 18.3 months with placebo to 25.8 months with denosumab (HR, 0.71; P = .004), corresponding to a 29% risk reduction, reported Dr. Fred Saad, professor and chief of urology at the University of Montreal Hospital Centre.

Discussant Dr. Eric Small, codirector of urologic oncology at the University of California, San Francisco, said that the study validates PSADT as an important risk stratifier in this group of patients, but observed that denosumab is not approved for this indication, and it appears to have the greatest benefit in a diminishingly small group of patients with shorter and shorter PSA doubling times.

"This is wonderful hypothesis generation, but cannot be used for the basis of therapeutic decisions," he said.

Bone metastasis–free survival in the entire cohort was 25.2 months with placebo and 29.5 months with denosumab (HR, 0.85; P = .028).

In February, an FDA advisory panel voted that denosumab does not have a favorable risk-benefit profile as a treatment to reduce the risk of bone metastasis in high-risk men (defined as those with a PSA level of at least 8.0 ng/mL or a PSA that doubled within 10 months or less).

Multimodal Benefit Goes 10 Years

The survival benefit of adding radiotherapy (RT) to androgen deprivation therapy (ADT) was maintained at 10 years in men with locally advanced prostate cancer, according to the final analysis of a phase III intergroup trial carried out by the U.K. Medical Research Council, the National Cancer Institute of Canada, and the Southwest Oncology Group.

At 10 years, 55% of men who were treated with ADT plus RT were alive, compared with 49% given ADT alone (HR, 0.70; P = .0003). The difference in disease-specific survival was particularly striking at 15% vs. 26%, favoring the combination (HR, 0.46; P less than .0001).

"That’s more than halving the risk of death from prostate cancer," said Prof. Malcolm D. Mason, head of oncology and palliative medicine at Cardiff (Wales) University.

In an interim analysis reported at ASCO 2010, RT plus ADT provided significant improvements at 7 years in overall survival (HR, 0.77; P = .033) and disease-specific survival (DSS; HR, 0.54; P = .0001).

In the current analysis, bowel and urinary morbidity were transiently elevated with the addition of radiation, most often delivered at a dose of 65-69 Gy, but were no different after 3 years.

An exploratory analysis favored whole pelvic vs. prostate-only radiation for overall survival (HR, 0.90; P = .57) and DSS (HR, 0.65; P = .15), but Dr. Mason called this finding hypothesis generating.

He remarked that combined ADT plus RT is enshrined in the European Association of Urology and National Comprehensive Cancer Network guidelines, "but that uptake is uncertain, and we have concerns as to whether this has been taken up as much as it should have been."

Dr. Small agreed with the authors’ conclusion that ADT and RT should be offered to all men with locally advanced prostate cancer suitable for RT, but said the absolute difference in 10-year overall-survival is modest, at 6%. Because accrual took place 10 years ago, the results also cannot be fully extrapolated to the increasingly common high-risk patients seen in the United States, who tend to be at a high grade and lower stage.

He pointed out that the combination arm had a 5% absolute increase in deaths because of secondary malignancies, which warrants exploration. "It makes you wonder what the radiation is doing here," he added.

Still, Dr. Small commended the authors for persevering with what he described as a tough study to do with a nonradiation arm. "This study is a demonstration of the power of the cooperative groups, and in an era of shrinking resources, points out that undersourcing the cooperative groups – as has been advocated by some – is shortsighted," he said.

Atrasentan Flops Again

Dr. David I. Quinn had the unenviable task of delivering the final word on atrasentan (Xinlay) as a prostate cancer therapy. The selective endothelin blocker failed as monotherapy in two previous phase III trials, and was so ineffective in combination with docetaxel that the phase III Southwest Oncology Group S0421 trial in advanced castration-resistant disease was halted early last year.

A new post hoc analysis from S0421 identified an 8-month survival benefit with atrasentan in a distinct subset of poor-prognosis patients with skeletal metastases and four bone metabolism biomarkers (median, 13 months vs. 5 months; P = .02).

Still, the drug proved futile when compared with docetaxel plus placebo in the entire cohort for time to progression (median, 9 months for both; HR, 1.03; P = .71) and overall survival (median, 18 months for both; HR, 1.04; P = .61). The 2-year progression-free survival was 18% in both groups, and overall survival rates were 37% and 38%, respectively.

"Endothelin blockade with currently available drugs such as atrasentan and zibotentan, which has three negative studies, is now a failed experiment," said Dr. Quinn, coleader of genitourinary medical oncology at the University of Southern California, Los Angeles. "It has been superseded by osteoblast-targeted therapy that actually works, like radium-223."

Dr. Parker reported consulting or advising for Algeta and receiving honoraria from Bayer; his coauthors reported financial relationships including employment with Algeta, which initiated the ALSYMPCA trial. Dr. Saad reported consulting or advising for and receiving honorarium and research funding from Amgen. Dr. Mason reported no disclosures. Dr. Quinn reported financial relationships with several firms. SWOG S0421 was supported by the Eastern Cooperative Oncology Group and Cancer and Leukemia Group B. Dr. Small reported consulting or advising for Dendreon and receiving research funding from Genzyme and Sanofi.