FDA Advisory Committee Meeting

SILVER SPRING, MD. – The decision on whether to approve the PARP inhibitor olaparib as maintenance treatment for a subgroup of women with platinum-sensitive relapsed ovarian cancer should be delayed until the results of a phase III study are available, according to the majority of a Food and Drug Administration advisory panel.

At a meeting of the FDA’s Oncologic Drugs Advisory Committee on June 25, it voted 11-2 that the effects of treatment – which included a median 7-month benefit in progression-free survival (PFS) over placebo in a subgroup of patients with ovarian cancer who have the germline BRCA (gBRCA) mutation in a phase II study – did not support an accelerated approval and that the decision should be delayed until the results of an ongoing phase III confirmatory study are available. The results of that study, the Study of Olaparib in Ovarian Cancer (SOLO) 2, are expected in mid-2016.

The FDA grants accelerated approval for drugs that treat serious or life-threatening conditions when there is evidence they provide a meaningful benefit over existing treatments, with endpoints considered "reasonably likely" to predict clinical benefit. The benefits, however, must be verified in a confirmatory trial. Otherwise, approval can be withdrawn. Because of multiple issues in the phase II study, including questions about the validity of the effects, statistical issues, and the potential for serious risks of the drug in a group of patients who otherwise may not be receiving treatment, the agency convened the panel meeting.

Olaparib – an inhibitor of poly ADP ribose polymerase (PARP), a key enzyme in one of the DNA repair pathways in human cells – "exploits tumor DNA repair pathway deficiencies to selectively induce cancer cell death," according to the manufacturer, AstraZeneca Pharmaceuticals. The proposed indication for olaparib, which is orally administered as monotherapy, is for "the maintenance treatment of adults with platinum-sensitive relapsed ovarian cancer (including fallopian tube or primary peritoneal) with germline BRCA (gBRCA) mutation as detected by an FDA-approved test, who are in response (complete response or partial response) to platinum-based chemotherapy."

The indication is based on a subgroup analysis of 96 patients with the gBRCA mutation who were enrolled in a phase II study of 265 women with platinum-sensitive relapsed high-grade ovarian cancer, randomized to treatment with olaparib or placebo as maintenance treatment after chemotherapy. In the study overall, the median PFS was 8.4 months for those on olaparib vs. 4.8 months among those on placebo, a statistically significant difference (hazard ratio, 0.35). In the 96 patients with the gBRCA mutation, however, the median PFS was 11.2 months among those on olaparib vs. 4.1 months among those on placebo, a significant difference (HR, 0.17).

Common adverse events included nausea, fatigue, abdominal pain, diarrhea and anemia – most were grade 1 or 2 but lasted a long time. Patients on olaparib experienced nausea for a median of 96 days, compared with 26 days among those on placebo. The median duration of other GI side effects also was higher among treated patients, including abdominal distension (147 vs. 34 days), constipation (44 vs. 4 days), and abdominal pain (75 vs. 18 days).

Among the issues raised by the FDA reviewers were the small number of patients with the mutation in the study, retrospective identification of most of those patients, and the possible imbalance in unknown prognostic factors between the treatment and placebo groups, as well as safety concerns – including the potentially increased risk of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) associated with treatment, considering the biology of the drug and cases reported in olaparib-treated patients.

In the study, there were four cases of MDS or AML, three in treated patients (2.2%). In a safety database of 2,618 patients treated with olaparib, there have been 22 cases of MDS or AML (0.8%).

Voting to delay approval, Dr. William McGuire III, medical director of gynecologic cancer outreach at Inova Fairfax Hospital in Falls Church, Va., said that he was conflicted, but was concerned because there is still no survival advantage evident. "This is a group of patients [with platinum-sensitive disease] that have generally good survival ... and I am most concerned about the possible signal that this drug may cause AML and MDS," which, he pointed out, "could actually lead to an early death in a patient who otherwise might live for a longer period of time."

Also voting with the majority, the panel chair, Dr. Mikkael Sekeres, director of the leukemia program at the Cleveland Clinic Taussig Cancer Institute, said that he was "extremely concerned about the risk of secondary cancers in ovarian cancer patients, who otherwise would receive no therapy at all," and that some of the secondary cancers may have been underreported. In addition, he said, "I was troubled about causing women months of nausea or other gastrointestinal side effects during a period of time they would otherwise be spending away from hospitals or clinics enjoying their lives."

One of the two panelists in favor of accelerated approval, Dr. Edward Trimble, director of the Center for Global Health at the National Cancer Institute, Rockville, Md., said that, in his view, the drug had a positive risk-benefit profile. It would be given to a limited number of ovarian cancer patients, was associated with a prolonged disease-free interval in the study, "and protected those patients from going on to intravenous cytotoxic therapy." The availability of an oral maintenance drug would make it possible for patients to avoid having to go to the hospital for chemotherapy for a period of time, which would be "a significant clinical benefit," he added.

SOLO 2 is an international, double-blind placebo-controlled randomized study comparing olaparib to placebo as maintenance therapy in 264* women with platinum-sensitive relapsed ovarian cancer and the gBRCA mutation. The study is evaluating a lower-dose, 300-mg-twice-a-day tablet formulation of olaparib.

The FDA is expected to make a decision by early October. The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts, although occasionally a panelist is given a waiver.

emechcatie@frontlinemednews.com

*CORRECTION, 6/26/2014: An earlier version of this story misstated the number of patients enrolled in the SOLO 2 trial.

SILVER SPRING, MD. – The decision on whether to approve the PARP inhibitor olaparib as maintenance treatment for a subgroup of women with platinum-sensitive relapsed ovarian cancer should be delayed until the results of a phase III study are available, according to the majority of a Food and Drug Administration advisory panel.

At a meeting of the FDA’s Oncologic Drugs Advisory Committee on June 25, it voted 11-2 that the effects of treatment – which included a median 7-month benefit in progression-free survival (PFS) over placebo in a subgroup of patients with ovarian cancer who have the germline BRCA (gBRCA) mutation in a phase II study – did not support an accelerated approval and that the decision should be delayed until the results of an ongoing phase III confirmatory study are available. The results of that study, the Study of Olaparib in Ovarian Cancer (SOLO) 2, are expected in mid-2016.

The FDA grants accelerated approval for drugs that treat serious or life-threatening conditions when there is evidence they provide a meaningful benefit over existing treatments, with endpoints considered "reasonably likely" to predict clinical benefit. The benefits, however, must be verified in a confirmatory trial. Otherwise, approval can be withdrawn. Because of multiple issues in the phase II study, including questions about the validity of the effects, statistical issues, and the potential for serious risks of the drug in a group of patients who otherwise may not be receiving treatment, the agency convened the panel meeting.

Olaparib – an inhibitor of poly ADP ribose polymerase (PARP), a key enzyme in one of the DNA repair pathways in human cells – "exploits tumor DNA repair pathway deficiencies to selectively induce cancer cell death," according to the manufacturer, AstraZeneca Pharmaceuticals. The proposed indication for olaparib, which is orally administered as monotherapy, is for "the maintenance treatment of adults with platinum-sensitive relapsed ovarian cancer (including fallopian tube or primary peritoneal) with germline BRCA (gBRCA) mutation as detected by an FDA-approved test, who are in response (complete response or partial response) to platinum-based chemotherapy."

The indication is based on a subgroup analysis of 96 patients with the gBRCA mutation who were enrolled in a phase II study of 265 women with platinum-sensitive relapsed high-grade ovarian cancer, randomized to treatment with olaparib or placebo as maintenance treatment after chemotherapy. In the study overall, the median PFS was 8.4 months for those on olaparib vs. 4.8 months among those on placebo, a statistically significant difference (hazard ratio, 0.35). In the 96 patients with the gBRCA mutation, however, the median PFS was 11.2 months among those on olaparib vs. 4.1 months among those on placebo, a significant difference (HR, 0.17).

Common adverse events included nausea, fatigue, abdominal pain, diarrhea and anemia – most were grade 1 or 2 but lasted a long time. Patients on olaparib experienced nausea for a median of 96 days, compared with 26 days among those on placebo. The median duration of other GI side effects also was higher among treated patients, including abdominal distension (147 vs. 34 days), constipation (44 vs. 4 days), and abdominal pain (75 vs. 18 days).

Among the issues raised by the FDA reviewers were the small number of patients with the mutation in the study, retrospective identification of most of those patients, and the possible imbalance in unknown prognostic factors between the treatment and placebo groups, as well as safety concerns – including the potentially increased risk of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) associated with treatment, considering the biology of the drug and cases reported in olaparib-treated patients.

In the study, there were four cases of MDS or AML, three in treated patients (2.2%). In a safety database of 2,618 patients treated with olaparib, there have been 22 cases of MDS or AML (0.8%).

Voting to delay approval, Dr. William McGuire III, medical director of gynecologic cancer outreach at Inova Fairfax Hospital in Falls Church, Va., said that he was conflicted, but was concerned because there is still no survival advantage evident. "This is a group of patients [with platinum-sensitive disease] that have generally good survival ... and I am most concerned about the possible signal that this drug may cause AML and MDS," which, he pointed out, "could actually lead to an early death in a patient who otherwise might live for a longer period of time."

Also voting with the majority, the panel chair, Dr. Mikkael Sekeres, director of the leukemia program at the Cleveland Clinic Taussig Cancer Institute, said that he was "extremely concerned about the risk of secondary cancers in ovarian cancer patients, who otherwise would receive no therapy at all," and that some of the secondary cancers may have been underreported. In addition, he said, "I was troubled about causing women months of nausea or other gastrointestinal side effects during a period of time they would otherwise be spending away from hospitals or clinics enjoying their lives."

One of the two panelists in favor of accelerated approval, Dr. Edward Trimble, director of the Center for Global Health at the National Cancer Institute, Rockville, Md., said that, in his view, the drug had a positive risk-benefit profile. It would be given to a limited number of ovarian cancer patients, was associated with a prolonged disease-free interval in the study, "and protected those patients from going on to intravenous cytotoxic therapy." The availability of an oral maintenance drug would make it possible for patients to avoid having to go to the hospital for chemotherapy for a period of time, which would be "a significant clinical benefit," he added.

SOLO 2 is an international, double-blind placebo-controlled randomized study comparing olaparib to placebo as maintenance therapy in 264* women with platinum-sensitive relapsed ovarian cancer and the gBRCA mutation. The study is evaluating a lower-dose, 300-mg-twice-a-day tablet formulation of olaparib.

The FDA is expected to make a decision by early October. The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts, although occasionally a panelist is given a waiver.

emechcatie@frontlinemednews.com

*CORRECTION, 6/26/2014: An earlier version of this story misstated the number of patients enrolled in the SOLO 2 trial.

SILVER SPRING, MD. – The decision on whether to approve the PARP inhibitor olaparib as maintenance treatment for a subgroup of women with platinum-sensitive relapsed ovarian cancer should be delayed until the results of a phase III study are available, according to the majority of a Food and Drug Administration advisory panel.

At a meeting of the FDA’s Oncologic Drugs Advisory Committee on June 25, it voted 11-2 that the effects of treatment – which included a median 7-month benefit in progression-free survival (PFS) over placebo in a subgroup of patients with ovarian cancer who have the germline BRCA (gBRCA) mutation in a phase II study – did not support an accelerated approval and that the decision should be delayed until the results of an ongoing phase III confirmatory study are available. The results of that study, the Study of Olaparib in Ovarian Cancer (SOLO) 2, are expected in mid-2016.

The FDA grants accelerated approval for drugs that treat serious or life-threatening conditions when there is evidence they provide a meaningful benefit over existing treatments, with endpoints considered "reasonably likely" to predict clinical benefit. The benefits, however, must be verified in a confirmatory trial. Otherwise, approval can be withdrawn. Because of multiple issues in the phase II study, including questions about the validity of the effects, statistical issues, and the potential for serious risks of the drug in a group of patients who otherwise may not be receiving treatment, the agency convened the panel meeting.

Olaparib – an inhibitor of poly ADP ribose polymerase (PARP), a key enzyme in one of the DNA repair pathways in human cells – "exploits tumor DNA repair pathway deficiencies to selectively induce cancer cell death," according to the manufacturer, AstraZeneca Pharmaceuticals. The proposed indication for olaparib, which is orally administered as monotherapy, is for "the maintenance treatment of adults with platinum-sensitive relapsed ovarian cancer (including fallopian tube or primary peritoneal) with germline BRCA (gBRCA) mutation as detected by an FDA-approved test, who are in response (complete response or partial response) to platinum-based chemotherapy."

The indication is based on a subgroup analysis of 96 patients with the gBRCA mutation who were enrolled in a phase II study of 265 women with platinum-sensitive relapsed high-grade ovarian cancer, randomized to treatment with olaparib or placebo as maintenance treatment after chemotherapy. In the study overall, the median PFS was 8.4 months for those on olaparib vs. 4.8 months among those on placebo, a statistically significant difference (hazard ratio, 0.35). In the 96 patients with the gBRCA mutation, however, the median PFS was 11.2 months among those on olaparib vs. 4.1 months among those on placebo, a significant difference (HR, 0.17).

Common adverse events included nausea, fatigue, abdominal pain, diarrhea and anemia – most were grade 1 or 2 but lasted a long time. Patients on olaparib experienced nausea for a median of 96 days, compared with 26 days among those on placebo. The median duration of other GI side effects also was higher among treated patients, including abdominal distension (147 vs. 34 days), constipation (44 vs. 4 days), and abdominal pain (75 vs. 18 days).

Among the issues raised by the FDA reviewers were the small number of patients with the mutation in the study, retrospective identification of most of those patients, and the possible imbalance in unknown prognostic factors between the treatment and placebo groups, as well as safety concerns – including the potentially increased risk of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) associated with treatment, considering the biology of the drug and cases reported in olaparib-treated patients.

In the study, there were four cases of MDS or AML, three in treated patients (2.2%). In a safety database of 2,618 patients treated with olaparib, there have been 22 cases of MDS or AML (0.8%).

Voting to delay approval, Dr. William McGuire III, medical director of gynecologic cancer outreach at Inova Fairfax Hospital in Falls Church, Va., said that he was conflicted, but was concerned because there is still no survival advantage evident. "This is a group of patients [with platinum-sensitive disease] that have generally good survival ... and I am most concerned about the possible signal that this drug may cause AML and MDS," which, he pointed out, "could actually lead to an early death in a patient who otherwise might live for a longer period of time."

Also voting with the majority, the panel chair, Dr. Mikkael Sekeres, director of the leukemia program at the Cleveland Clinic Taussig Cancer Institute, said that he was "extremely concerned about the risk of secondary cancers in ovarian cancer patients, who otherwise would receive no therapy at all," and that some of the secondary cancers may have been underreported. In addition, he said, "I was troubled about causing women months of nausea or other gastrointestinal side effects during a period of time they would otherwise be spending away from hospitals or clinics enjoying their lives."

One of the two panelists in favor of accelerated approval, Dr. Edward Trimble, director of the Center for Global Health at the National Cancer Institute, Rockville, Md., said that, in his view, the drug had a positive risk-benefit profile. It would be given to a limited number of ovarian cancer patients, was associated with a prolonged disease-free interval in the study, "and protected those patients from going on to intravenous cytotoxic therapy." The availability of an oral maintenance drug would make it possible for patients to avoid having to go to the hospital for chemotherapy for a period of time, which would be "a significant clinical benefit," he added.

SOLO 2 is an international, double-blind placebo-controlled randomized study comparing olaparib to placebo as maintenance therapy in 264* women with platinum-sensitive relapsed ovarian cancer and the gBRCA mutation. The study is evaluating a lower-dose, 300-mg-twice-a-day tablet formulation of olaparib.

The FDA is expected to make a decision by early October. The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts, although occasionally a panelist is given a waiver.

emechcatie@frontlinemednews.com

*CORRECTION, 6/26/2014: An earlier version of this story misstated the number of patients enrolled in the SOLO 2 trial.