Bevacizumab, other targeted drugs, and poly (ADP-ribose) polymerase (PARP) inhibitors with or without chemotherapy

The Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Diseases (OCEANS [NCT00434642]) assessed the role of bevacizumab in the treatment of platinum-sensitive recurrence (see Table 8 for other trials in this setting). In this double-blind, placebo-controlled, phase III trial of chemotherapy (gemcitabine plus carboplatin) with or without bevacizumab for recurrent ovarian epithelial cancer, FTC, or PPC, 242 patients were randomly assigned to each arm. In contrast to the first-line studies, treatment was allowed to continue beyond six cycles to ten cycles in responding patients, but there was no maintenance therapy.[24]

The Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Diseases (OCEANS [NCT00434642]) assessed the role of bevacizumab in the treatment of platinum-sensitive recurrence (see Table 8 for other trials in this setting). In this double-blind, placebo-controlled, phase III trial of chemotherapy (gemcitabine plus carboplatin) with or without bevacizumab for recurrent ovarian epithelial cancer, FTC, or PPC, 242 patients were randomly assigned to each arm. In contrast to the first-line studies, treatment was allowed to continue beyond six cycles to ten cycles in responding patients, but there was no maintenance therapy.[24]

A subsequent analysis will appear when additional survival data become mature; however, at the time of publication, differences in median OS were not apparent, and crossover from a placebo to bevacizumab had occurred in 31% of the patients.

The Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Diseases (OCEANS [NCT00434642]) assessed the role of bevacizumab in the treatment of platinum-sensitive recurrence (see Table 8 for other trials in this setting). In this double-blind, placebo-controlled, phase III trial of chemotherapy (gemcitabine plus carboplatin) with or without bevacizumab for recurrent ovarian epithelial cancer, FTC, or PPC, 242 patients were randomly assigned to each arm. In contrast to the first-line studies, treatment was allowed to continue beyond six cycles to ten cycles in responding patients, but there was no maintenance therapy.[24]

Median PFS for patients receiving bevacizumab was 12.4 months versus 8.4 months for those receiving a placebo.

The Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Diseases (OCEANS [NCT00434642]) assessed the role of bevacizumab in the treatment of platinum-sensitive recurrence (see Table 8 for other trials in this setting). In this double-blind, placebo-controlled, phase III trial of chemotherapy (gemcitabine plus carboplatin) with or without bevacizumab for recurrent ovarian epithelial cancer, FTC, or PPC, 242 patients were randomly assigned to each arm. In contrast to the first-line studies, treatment was allowed to continue beyond six cycles to ten cycles in responding patients, but there was no maintenance therapy.[24]

The HR for the effect of bevacizumab on disease progression in patients assigned to the bevacizumab arm compared with placebo was 0.484 (95% CI, 0.388–0.605; P < .0001).

The Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Diseases (OCEANS [NCT00434642]) assessed the role of bevacizumab in the treatment of platinum-sensitive recurrence (see Table 8 for other trials in this setting). In this double-blind, placebo-controlled, phase III trial of chemotherapy (gemcitabine plus carboplatin) with or without bevacizumab for recurrent ovarian epithelial cancer, FTC, or PPC, 242 patients were randomly assigned to each arm. In contrast to the first-line studies, treatment was allowed to continue beyond six cycles to ten cycles in responding patients, but there was no maintenance therapy.[24]

Objective responses to chemotherapy were increased when combined with bevacizumab (78.5% vs. 57.4%; P < .0001).

The Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Diseases (OCEANS [NCT00434642]) assessed the role of bevacizumab in the treatment of platinum-sensitive recurrence (see Table 8 for other trials in this setting). In this double-blind, placebo-controlled, phase III trial of chemotherapy (gemcitabine plus carboplatin) with or without bevacizumab for recurrent ovarian epithelial cancer, FTC, or PPC, 242 patients were randomly assigned to each arm. In contrast to the first-line studies, treatment was allowed to continue beyond six cycles to ten cycles in responding patients, but there was no maintenance therapy.[24]

Bevacizumab-associated toxicities such as hypertension and proteinuria were more prominent than in the first-line trials, but feared safety issues such as gastrointestinal perforations did not occur during the study.

The Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Diseases (OCEANS [NCT00434642]) assessed the role of bevacizumab in the treatment of platinum-sensitive recurrence (see Table 8 for other trials in this setting). In this double-blind, placebo-controlled, phase III trial of chemotherapy (gemcitabine plus carboplatin) with or without bevacizumab for recurrent ovarian epithelial cancer, FTC, or PPC, 242 patients were randomly assigned to each arm. In contrast to the first-line studies, treatment was allowed to continue beyond six cycles to ten cycles in responding patients, but there was no maintenance therapy.[24]

Treatment discontinuation because of adverse events was more common for patients who received bevacizumab than placebo (55 vs. 12), but fewer patients discontinued treatment because of disease progression (104 vs. 160).

NRG Oncology Group, or National Clinical Trials Network group, a combined research effort of the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the GOG (GOG-0213 [NCT00565851]) assessed both the role of surgical debulking and the addition of bevacizumab induction and maintenance in women with platinum-sensitive recurrences of ovarian cancer.[7][Level of evidence A1] The nonsurgical portion of GOG-0213 had 81% power for a true HR of 0.75; it enrolled 674 women from 2007 to 2011, and the published analysis took place after a median follow-up exceeding 4 years.

NRG Oncology Group, or National Clinical Trials Network group, a combined research effort of the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the GOG (GOG-0213 [NCT00565851]) assessed both the role of surgical debulking and the addition of bevacizumab induction and maintenance in women with platinum-sensitive recurrences of ovarian cancer.[7][Level of evidence A1] The nonsurgical portion of GOG-0213 had 81% power for a true HR of 0.75; it enrolled 674 women from 2007 to 2011, and the published analysis took place after a median follow-up exceeding 4 years.

OS was not significantly different: 37.3 months (95% CI, 32.6–39.7) versus 42.2 months (95% CI, 37.7–46.2).

NRG Oncology Group, or National Clinical Trials Network group, a combined research effort of the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the GOG (GOG-0213 [NCT00565851]) assessed both the role of surgical debulking and the addition of bevacizumab induction and maintenance in women with platinum-sensitive recurrences of ovarian cancer.[7][Level of evidence A1] The nonsurgical portion of GOG-0213 had 81% power for a true HR of 0.75; it enrolled 674 women from 2007 to 2011, and the published analysis took place after a median follow-up exceeding 4 years.

The secondary end point of median PFS was significantly in favor of the addition of bevacizumab: 10.4 months (95% CI, 9.7–11) for chemotherapy alone versus 13.8 months (95% CI, 13.0–14.7).

NRG Oncology Group, or National Clinical Trials Network group, a combined research effort of the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the GOG (GOG-0213 [NCT00565851]) assessed both the role of surgical debulking and the addition of bevacizumab induction and maintenance in women with platinum-sensitive recurrences of ovarian cancer.[7][Level of evidence A1] The nonsurgical portion of GOG-0213 had 81% power for a true HR of 0.75; it enrolled 674 women from 2007 to 2011, and the published analysis took place after a median follow-up exceeding 4 years.

Bevacizumab (15 mg/kg q 3 weeks) with chemotherapy and its use in maintenance led to an excess of grade 3 and 4 adverse events (8% for chemotherapy alone vs. 30%), any bleeding (12% vs. 42%), and any hypertension (3% vs. 41%).

In an open-label, randomized, phase III trial (MITO16b/MANGO-OV2/ENGOT-ov17 [NCT01802749]), investigators enrolled 406 patients at first recurrence or progression at least 6 months after receiving first-line platinum-based treatment, including bevacizumab during induction or maintenance.[17] The trial compared carboplatin doublets with or without bevacizumab as standard treatment for patients with platinum-sensitive recurrence. Dosing schedules varied with each doublet and all bevacizumab was given at a dose rate of 5 mg/kg/week. Twenty-one patients received carboplatin/paclitaxel, and 22 patients received carboplatin/paclitaxel plus bevacizumab; 99 patients received cisplatin/gemcitabine, and 98 patients received cisplatin/gemcitabine plus bevacizumab; and 83 patients received pegylated liposomal doxorubicin, and 83 patients received pegylated liposomal doxorubicin plus bevacizumab. The primary end point was investigator-assessed PFS, seeking to reduce the HR for recurrence to 0.67 (90% power and two-tailed test at alpha = .05). Secondary end points were OS (from time of randomization to death from any cause) and objective response rates according to Response Evaluation Criteria in Solid Tumors (RECIST). The study demonstrated that the addition of bevacizumab improved PFS but did not result in any OS benefit and was associated with increased toxicity. This study preceded incorporation of PARP inhibitors in phase III trials for patients with platinum-sensitive recurrence. In a subset analysis of patients with BRCA variants in this study, only 23 patients in the standard arm and 30 patients in the chemotherapy-plus-bevacizumab arm had documented deleterious variants. These details underscore the evolution of targeted treatment that has occurred during and after this study.

In an open-label, randomized, phase III trial (MITO16b/MANGO-OV2/ENGOT-ov17 [NCT01802749]), investigators enrolled 406 patients at first recurrence or progression at least 6 months after receiving first-line platinum-based treatment, including bevacizumab during induction or maintenance.[17] The trial compared carboplatin doublets with or without bevacizumab as standard treatment for patients with platinum-sensitive recurrence. Dosing schedules varied with each doublet and all bevacizumab was given at a dose rate of 5 mg/kg/week. Twenty-one patients received carboplatin/paclitaxel, and 22 patients received carboplatin/paclitaxel plus bevacizumab; 99 patients received cisplatin/gemcitabine, and 98 patients received cisplatin/gemcitabine plus bevacizumab; and 83 patients received pegylated liposomal doxorubicin, and 83 patients received pegylated liposomal doxorubicin plus bevacizumab. The primary end point was investigator-assessed PFS, seeking to reduce the HR for recurrence to 0.67 (90% power and two-tailed test at alpha = .05). Secondary end points were OS (from time of randomization to death from any cause) and objective response rates according to Response Evaluation Criteria in Solid Tumors (RECIST). The study demonstrated that the addition of bevacizumab improved PFS but did not result in any OS benefit and was associated with increased toxicity. This study preceded incorporation of PARP inhibitors in phase III trials for patients with platinum-sensitive recurrence. In a subset analysis of patients with BRCA variants in this study, only 23 patients in the standard arm and 30 patients in the chemotherapy-plus-bevacizumab arm had documented deleterious variants. These details underscore the evolution of targeted treatment that has occurred during and after this study.

Median PFS was 8.8 months (95% CI, 8.4–9.3) for patients in the standard chemotherapy arm versus 11.8 months (HR, 0.51; 95% CI, 10.8–12.9) for patients in the chemotherapy-plus-bevacizumab arm.[17][Level of evidence B1]

In an open-label, randomized, phase III trial (MITO16b/MANGO-OV2/ENGOT-ov17 [NCT01802749]), investigators enrolled 406 patients at first recurrence or progression at least 6 months after receiving first-line platinum-based treatment, including bevacizumab during induction or maintenance.[17] The trial compared carboplatin doublets with or without bevacizumab as standard treatment for patients with platinum-sensitive recurrence. Dosing schedules varied with each doublet and all bevacizumab was given at a dose rate of 5 mg/kg/week. Twenty-one patients received carboplatin/paclitaxel, and 22 patients received carboplatin/paclitaxel plus bevacizumab; 99 patients received cisplatin/gemcitabine, and 98 patients received cisplatin/gemcitabine plus bevacizumab; and 83 patients received pegylated liposomal doxorubicin, and 83 patients received pegylated liposomal doxorubicin plus bevacizumab. The primary end point was investigator-assessed PFS, seeking to reduce the HR for recurrence to 0.67 (90% power and two-tailed test at alpha = .05). Secondary end points were OS (from time of randomization to death from any cause) and objective response rates according to Response Evaluation Criteria in Solid Tumors (RECIST). The study demonstrated that the addition of bevacizumab improved PFS but did not result in any OS benefit and was associated with increased toxicity. This study preceded incorporation of PARP inhibitors in phase III trials for patients with platinum-sensitive recurrence. In a subset analysis of patients with BRCA variants in this study, only 23 patients in the standard arm and 30 patients in the chemotherapy-plus-bevacizumab arm had documented deleterious variants. These details underscore the evolution of targeted treatment that has occurred during and after this study.

OS was not different between the two groups: median OS was 27.1 months for patients in the standard arm versus 26.7 months for patients in the chemotherapy-plus-bevacizumab arm.

In an open-label, randomized, phase III trial (MITO16b/MANGO-OV2/ENGOT-ov17 [NCT01802749]), investigators enrolled 406 patients at first recurrence or progression at least 6 months after receiving first-line platinum-based treatment, including bevacizumab during induction or maintenance.[17] The trial compared carboplatin doublets with or without bevacizumab as standard treatment for patients with platinum-sensitive recurrence. Dosing schedules varied with each doublet and all bevacizumab was given at a dose rate of 5 mg/kg/week. Twenty-one patients received carboplatin/paclitaxel, and 22 patients received carboplatin/paclitaxel plus bevacizumab; 99 patients received cisplatin/gemcitabine, and 98 patients received cisplatin/gemcitabine plus bevacizumab; and 83 patients received pegylated liposomal doxorubicin, and 83 patients received pegylated liposomal doxorubicin plus bevacizumab. The primary end point was investigator-assessed PFS, seeking to reduce the HR for recurrence to 0.67 (90% power and two-tailed test at alpha = .05). Secondary end points were OS (from time of randomization to death from any cause) and objective response rates according to Response Evaluation Criteria in Solid Tumors (RECIST). The study demonstrated that the addition of bevacizumab improved PFS but did not result in any OS benefit and was associated with increased toxicity. This study preceded incorporation of PARP inhibitors in phase III trials for patients with platinum-sensitive recurrence. In a subset analysis of patients with BRCA variants in this study, only 23 patients in the standard arm and 30 patients in the chemotherapy-plus-bevacizumab arm had documented deleterious variants. These details underscore the evolution of targeted treatment that has occurred during and after this study.

Objective response rate analysis determined that 71 of 143 patients in the standard arm and 90 of 130 patients in the chemotherapy-plus-bevacizumab arm had either complete or partial responses.

In an open-label, randomized, phase III trial (MITO16b/MANGO-OV2/ENGOT-ov17 [NCT01802749]), investigators enrolled 406 patients at first recurrence or progression at least 6 months after receiving first-line platinum-based treatment, including bevacizumab during induction or maintenance.[17] The trial compared carboplatin doublets with or without bevacizumab as standard treatment for patients with platinum-sensitive recurrence. Dosing schedules varied with each doublet and all bevacizumab was given at a dose rate of 5 mg/kg/week. Twenty-one patients received carboplatin/paclitaxel, and 22 patients received carboplatin/paclitaxel plus bevacizumab; 99 patients received cisplatin/gemcitabine, and 98 patients received cisplatin/gemcitabine plus bevacizumab; and 83 patients received pegylated liposomal doxorubicin, and 83 patients received pegylated liposomal doxorubicin plus bevacizumab. The primary end point was investigator-assessed PFS, seeking to reduce the HR for recurrence to 0.67 (90% power and two-tailed test at alpha = .05). Secondary end points were OS (from time of randomization to death from any cause) and objective response rates according to Response Evaluation Criteria in Solid Tumors (RECIST). The study demonstrated that the addition of bevacizumab improved PFS but did not result in any OS benefit and was associated with increased toxicity. This study preceded incorporation of PARP inhibitors in phase III trials for patients with platinum-sensitive recurrence. In a subset analysis of patients with BRCA variants in this study, only 23 patients in the standard arm and 30 patients in the chemotherapy-plus-bevacizumab arm had documented deleterious variants. These details underscore the evolution of targeted treatment that has occurred during and after this study.

The safety population included 200 patients in the standard arm and 201 patients in the chemotherapy-plus-bevacizumab arm. Numerous serious adverse events were recorded in both arms: 61 events for 41 patients in the standard arm and 76 events for 52 patients in the chemotherapy-plus-bevacizumab arm.

In an open-label, randomized, phase III trial (MITO16b/MANGO-OV2/ENGOT-ov17 [NCT01802749]), investigators enrolled 406 patients at first recurrence or progression at least 6 months after receiving first-line platinum-based treatment, including bevacizumab during induction or maintenance.[17] The trial compared carboplatin doublets with or without bevacizumab as standard treatment for patients with platinum-sensitive recurrence. Dosing schedules varied with each doublet and all bevacizumab was given at a dose rate of 5 mg/kg/week. Twenty-one patients received carboplatin/paclitaxel, and 22 patients received carboplatin/paclitaxel plus bevacizumab; 99 patients received cisplatin/gemcitabine, and 98 patients received cisplatin/gemcitabine plus bevacizumab; and 83 patients received pegylated liposomal doxorubicin, and 83 patients received pegylated liposomal doxorubicin plus bevacizumab. The primary end point was investigator-assessed PFS, seeking to reduce the HR for recurrence to 0.67 (90% power and two-tailed test at alpha = .05). Secondary end points were OS (from time of randomization to death from any cause) and objective response rates according to Response Evaluation Criteria in Solid Tumors (RECIST). The study demonstrated that the addition of bevacizumab improved PFS but did not result in any OS benefit and was associated with increased toxicity. This study preceded incorporation of PARP inhibitors in phase III trials for patients with platinum-sensitive recurrence. In a subset analysis of patients with BRCA variants in this study, only 23 patients in the standard arm and 30 patients in the chemotherapy-plus-bevacizumab arm had documented deleterious variants. These details underscore the evolution of targeted treatment that has occurred during and after this study.

Hypertension was a major adverse event. In the standard arm, 93% of patients experienced hypertension: 166 patients experienced grade 1 or 2 hypertension and 20 patients experienced grade 3 hypertension. In the chemotherapy-plus-bevacizumab arm, 98% of patients experienced hypertension: 139 patients experienced grade 1 or 2 hypertension and 58 patients experienced grade 3 hypertension.

In an open-label, randomized, phase III trial (MITO16b/MANGO-OV2/ENGOT-ov17 [NCT01802749]), investigators enrolled 406 patients at first recurrence or progression at least 6 months after receiving first-line platinum-based treatment, including bevacizumab during induction or maintenance.[17] The trial compared carboplatin doublets with or without bevacizumab as standard treatment for patients with platinum-sensitive recurrence. Dosing schedules varied with each doublet and all bevacizumab was given at a dose rate of 5 mg/kg/week. Twenty-one patients received carboplatin/paclitaxel, and 22 patients received carboplatin/paclitaxel plus bevacizumab; 99 patients received cisplatin/gemcitabine, and 98 patients received cisplatin/gemcitabine plus bevacizumab; and 83 patients received pegylated liposomal doxorubicin, and 83 patients received pegylated liposomal doxorubicin plus bevacizumab. The primary end point was investigator-assessed PFS, seeking to reduce the HR for recurrence to 0.67 (90% power and two-tailed test at alpha = .05). Secondary end points were OS (from time of randomization to death from any cause) and objective response rates according to Response Evaluation Criteria in Solid Tumors (RECIST). The study demonstrated that the addition of bevacizumab improved PFS but did not result in any OS benefit and was associated with increased toxicity. This study preceded incorporation of PARP inhibitors in phase III trials for patients with platinum-sensitive recurrence. In a subset analysis of patients with BRCA variants in this study, only 23 patients in the standard arm and 30 patients in the chemotherapy-plus-bevacizumab arm had documented deleterious variants. These details underscore the evolution of targeted treatment that has occurred during and after this study.

Proteinuria and epistaxis were also prominent grade 1 or 2 adverse events for patients in the chemotherapy-plus-bevacizumab arm.

In a randomized, double blind, placebo-controlled phase II trial of olaparib maintenance therapy, eligible patients had platinum-sensitive, high-grade serous ovarian cancer. Patients were randomly assigned to receive olaparib (400 mg bid) or placebo. Having germline BRCA1 or BRCA2 variants was not required for eligibility; however, 23% of patients in the experimental group and 22% of patients in the placebo group had known BRCA1 or BRCA2 variants. The primary end point was PFS.[27][Level of evidence B1]

In a randomized, double blind, placebo-controlled phase II trial of olaparib maintenance therapy, eligible patients had platinum-sensitive, high-grade serous ovarian cancer. Patients were randomly assigned to receive olaparib (400 mg bid) or placebo. Having germline BRCA1 or BRCA2 variants was not required for eligibility; however, 23% of patients in the experimental group and 22% of patients in the placebo group had known BRCA1 or BRCA2 variants. The primary end point was PFS.[27][Level of evidence B1]

Median PFS was 8.4 months for patients in the olaparib arm versus 4.8 months for patients in the placebo arm (HR, 0.35; 95% CI, 0.25–0.49; P < .001).

In a randomized, double blind, placebo-controlled phase II trial of olaparib maintenance therapy, eligible patients had platinum-sensitive, high-grade serous ovarian cancer. Patients were randomly assigned to receive olaparib (400 mg bid) or placebo. Having germline BRCA1 or BRCA2 variants was not required for eligibility; however, 23% of patients in the experimental group and 22% of patients in the placebo group had known BRCA1 or BRCA2 variants. The primary end point was PFS.[27][Level of evidence B1]

OS was not different between the two groups, as noted in an updated report.[28]

In a randomized, double blind, placebo-controlled phase II trial of olaparib maintenance therapy, eligible patients had platinum-sensitive, high-grade serous ovarian cancer. Patients were randomly assigned to receive olaparib (400 mg bid) or placebo. Having germline BRCA1 or BRCA2 variants was not required for eligibility; however, 23% of patients in the experimental group and 22% of patients in the placebo group had known BRCA1 or BRCA2 variants. The primary end point was PFS.[27][Level of evidence B1]

The more common adverse events in the olaparib group were nausea, fatigue, vomiting, and anemia.

Olaparib tablets (as opposed to the previous capsule formulation) underwent evaluation in SOLO2 (NCT01874353), a double-blind, randomized, placebo-controlled phase III trial in patients with high-grade serous or endometrioid cancer, PPC, or FTC. Patients had platinum-sensitive relapses and were preselected for BRCA1/BRCA2 variants.[29][Level of evidence B1] Stratification for response (complete vs. partial) to previous platinum and platinum-free intervals (>6–12 vs. >12 months) and 2:1 random allocation to olaparib in two 150-mg twice-daily or matching placebo tablets took place. Of 295 eligible patients enrolled, 196 were assigned to olaparib, and 99 were assigned to a placebo. The primary end point was PFS.

Olaparib tablets (as opposed to the previous capsule formulation) underwent evaluation in SOLO2 (NCT01874353), a double-blind, randomized, placebo-controlled phase III trial in patients with high-grade serous or endometrioid cancer, PPC, or FTC. Patients had platinum-sensitive relapses and were preselected for BRCA1/BRCA2 variants.[29][Level of evidence B1] Stratification for response (complete vs. partial) to previous platinum and platinum-free intervals (>6–12 vs. >12 months) and 2:1 random allocation to olaparib in two 150-mg twice-daily or matching placebo tablets took place. Of 295 eligible patients enrolled, 196 were assigned to olaparib, and 99 were assigned to a placebo. The primary end point was PFS.

PFS was 19.1 months (95% CI, 16.3–25.7) for the olaparib group and 5.5 months (range, 5.2–5.8) for the placebo group (HR, 0.30; 95% CI, 0.22–0.41; P < .0001).

Olaparib tablets (as opposed to the previous capsule formulation) underwent evaluation in SOLO2 (NCT01874353), a double-blind, randomized, placebo-controlled phase III trial in patients with high-grade serous or endometrioid cancer, PPC, or FTC. Patients had platinum-sensitive relapses and were preselected for BRCA1/BRCA2 variants.[29][Level of evidence B1] Stratification for response (complete vs. partial) to previous platinum and platinum-free intervals (>6–12 vs. >12 months) and 2:1 random allocation to olaparib in two 150-mg twice-daily or matching placebo tablets took place. Of 295 eligible patients enrolled, 196 were assigned to olaparib, and 99 were assigned to a placebo. The primary end point was PFS.

Serious adverse events occurred in 18% of patients who received olaparib and 8% of patients who received placebo. The most common adverse events were anemia, abdominal pain, and intestinal obstruction.

Olaparib tablets (as opposed to the previous capsule formulation) underwent evaluation in SOLO2 (NCT01874353), a double-blind, randomized, placebo-controlled phase III trial in patients with high-grade serous or endometrioid cancer, PPC, or FTC. Patients had platinum-sensitive relapses and were preselected for BRCA1/BRCA2 variants.[29][Level of evidence B1] Stratification for response (complete vs. partial) to previous platinum and platinum-free intervals (>6–12 vs. >12 months) and 2:1 random allocation to olaparib in two 150-mg twice-daily or matching placebo tablets took place. Of 295 eligible patients enrolled, 196 were assigned to olaparib, and 99 were assigned to a placebo. The primary end point was PFS.

In this trial, a comprehensive assessment of health-related quality-of-life measurements was carried out in patients who received olaparib compared with patients who received placebo.[30] The Trial Outcome Index score was used in a prespecified analysis of changes, showing that several measurements were met. In addition, time without significant symptoms of toxicity and quality-adjusted PFS were longer in patients who were treated with olaparib. These assessments supplement other measurements such as time to first treatment and time to subsequent therapy or death that have been sought to supplement PFS as a primary end point for drug approval.

The SOLO3 trial [NCT00628251], a phase III study that employed 2:1 randomization, compared olaparib tablets with physicians' choice of nonplatinum chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, gemcitabine, or topotecan) for the treatment of recurrent platinum-sensitive ovarian cancer and germline BRCA1 or BRCA2 variants.[31] A previous randomized phase II study of dose levels of olaparib capsules at either 200 or 400 mg twice daily versus pegylated liposomal doxorubicin had failed to show an advantage over chemotherapy.[32] In SOLO3, 178 patients were allocated to receive olaparib and 88 patients received physicians’ choice chemotherapy. The primary end point was overall response rate.

The SOLO3 trial [NCT00628251], a phase III study that employed 2:1 randomization, compared olaparib tablets with physicians' choice of nonplatinum chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, gemcitabine, or topotecan) for the treatment of recurrent platinum-sensitive ovarian cancer and germline BRCA1 or BRCA2 variants.[31] A previous randomized phase II study of dose levels of olaparib capsules at either 200 or 400 mg twice daily versus pegylated liposomal doxorubicin had failed to show an advantage over chemotherapy.[32] In SOLO3, 178 patients were allocated to receive olaparib and 88 patients received physicians’ choice chemotherapy. The primary end point was overall response rate.

Of 151 patients assessed, 109 had objective responses to olaparib (14 complete responses), whereas of 72 patients assessed, 37 had objective responses to chemotherapy (2 complete responses).

The SOLO3 trial [NCT00628251], a phase III study that employed 2:1 randomization, compared olaparib tablets with physicians' choice of nonplatinum chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, gemcitabine, or topotecan) for the treatment of recurrent platinum-sensitive ovarian cancer and germline BRCA1 or BRCA2 variants.[31] A previous randomized phase II study of dose levels of olaparib capsules at either 200 or 400 mg twice daily versus pegylated liposomal doxorubicin had failed to show an advantage over chemotherapy.[32] In SOLO3, 178 patients were allocated to receive olaparib and 88 patients received physicians’ choice chemotherapy. The primary end point was overall response rate.

At final analysis, there was no significant difference in OS. The median OS was 34.9 months for patients who received olaparib and 32.9 months for patients who received chemotherapy (HR, 1.07; P = .71).[33]

The SOLO3 trial [NCT00628251], a phase III study that employed 2:1 randomization, compared olaparib tablets with physicians' choice of nonplatinum chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, gemcitabine, or topotecan) for the treatment of recurrent platinum-sensitive ovarian cancer and germline BRCA1 or BRCA2 variants.[31] A previous randomized phase II study of dose levels of olaparib capsules at either 200 or 400 mg twice daily versus pegylated liposomal doxorubicin had failed to show an advantage over chemotherapy.[32] In SOLO3, 178 patients were allocated to receive olaparib and 88 patients received physicians’ choice chemotherapy. The primary end point was overall response rate.

A subgroup analysis of patients treated with at least three lines of chemotherapy showed a survival detriment. Among these patients, the median OS was 29.9 months in the olaparib group and 39.4 months in the chemotherapy group (HR, 1.33; 95% CI, 0.84–2.18).

The SOLO3 trial [NCT00628251], a phase III study that employed 2:1 randomization, compared olaparib tablets with physicians' choice of nonplatinum chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, gemcitabine, or topotecan) for the treatment of recurrent platinum-sensitive ovarian cancer and germline BRCA1 or BRCA2 variants.[31] A previous randomized phase II study of dose levels of olaparib capsules at either 200 or 400 mg twice daily versus pegylated liposomal doxorubicin had failed to show an advantage over chemotherapy.[32] In SOLO3, 178 patients were allocated to receive olaparib and 88 patients received physicians’ choice chemotherapy. The primary end point was overall response rate.

Adverse events were consistent with established safety profiles of olaparib and the chemotherapy comparators, but in this pretreated population, four patients assigned to receive olaparib and three patients assigned to receive chemotherapy developed acute myeloid leukemia (AML)/myelodysplasia; new primary malignancies also occurred in three patients assigned to receive olaparib.[31][Level of evidence B1]

The SOLO3 trial [NCT00628251], a phase III study that employed 2:1 randomization, compared olaparib tablets with physicians' choice of nonplatinum chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, gemcitabine, or topotecan) for the treatment of recurrent platinum-sensitive ovarian cancer and germline BRCA1 or BRCA2 variants.[31] A previous randomized phase II study of dose levels of olaparib capsules at either 200 or 400 mg twice daily versus pegylated liposomal doxorubicin had failed to show an advantage over chemotherapy.[32] In SOLO3, 178 patients were allocated to receive olaparib and 88 patients received physicians’ choice chemotherapy. The primary end point was overall response rate.

In 2022, AstraZeneca withdrew the indication for olaparib monotherapy for the treatment of patients with deleterious germline BRCA-altered ovarian cancer who have received at least three previous lines of chemotherapy.[34]

Rucaparib underwent phase II evaluation in ARIEL2 (NCT01891344), an open-label study enrolling 206 patients, 204 of whom were actually receiving the drug (192 were actually in classifiable subgroups) and had high-grade platinum-sensitive recurrences between October 2013 and November 2014.[35][Level of evidence C2] The following three predefined homologous recombination deficiency subgroups on the basis of tumor mutational analysis were studied: The drug was given orally at 600 mg twice daily, and patients were treated until disease progression or other reasons for discontinuation. Median duration of treatment for the 204 patients was 5.7 months.

Rucaparib underwent phase II evaluation in ARIEL2 (NCT01891344), an open-label study enrolling 206 patients, 204 of whom were actually receiving the drug (192 were actually in classifiable subgroups) and had high-grade platinum-sensitive recurrences between October 2013 and November 2014.[35][Level of evidence C2] The following three predefined homologous recombination deficiency subgroups on the basis of tumor mutational analysis were studied: The drug was given orally at 600 mg twice daily, and patients were treated until disease progression or other reasons for discontinuation. Median duration of treatment for the 204 patients was 5.7 months.

BRCA variant (deleterious genetic or somatic) (n = 40).

Rucaparib underwent phase II evaluation in ARIEL2 (NCT01891344), an open-label study enrolling 206 patients, 204 of whom were actually receiving the drug (192 were actually in classifiable subgroups) and had high-grade platinum-sensitive recurrences between October 2013 and November 2014.[35][Level of evidence C2] The following three predefined homologous recombination deficiency subgroups on the basis of tumor mutational analysis were studied: The drug was given orally at 600 mg twice daily, and patients were treated until disease progression or other reasons for discontinuation. Median duration of treatment for the 204 patients was 5.7 months.

BRCA wild type and high loss of heterozygosity (LOH) quantified by next-generation sequencing analysis (LOH high) (n = 82).

Rucaparib underwent phase II evaluation in ARIEL2 (NCT01891344), an open-label study enrolling 206 patients, 204 of whom were actually receiving the drug (192 were actually in classifiable subgroups) and had high-grade platinum-sensitive recurrences between October 2013 and November 2014.[35][Level of evidence C2] The following three predefined homologous recombination deficiency subgroups on the basis of tumor mutational analysis were studied: The drug was given orally at 600 mg twice daily, and patients were treated until disease progression or other reasons for discontinuation. Median duration of treatment for the 204 patients was 5.7 months.

BRCA wild type and low LOH (LOH low) (n = 70).

Rucaparib underwent phase II evaluation in ARIEL2 (NCT01891344), an open-label study enrolling 206 patients, 204 of whom were actually receiving the drug (192 were actually in classifiable subgroups) and had high-grade platinum-sensitive recurrences between October 2013 and November 2014.[35][Level of evidence C2] The following three predefined homologous recombination deficiency subgroups on the basis of tumor mutational analysis were studied: The drug was given orally at 600 mg twice daily, and patients were treated until disease progression or other reasons for discontinuation. Median duration of treatment for the 204 patients was 5.7 months.

Median PFS after the start of rucaparib treatment for patients with deleterious BRCA variants was 12.8 months (95% CI, 9.0–14.7); for those with LOH, high was 5.7 months (range, 5.3–7.6 months), and low was 5.2 months (range, 3.6–5.5 months).

Rucaparib underwent phase II evaluation in ARIEL2 (NCT01891344), an open-label study enrolling 206 patients, 204 of whom were actually receiving the drug (192 were actually in classifiable subgroups) and had high-grade platinum-sensitive recurrences between October 2013 and November 2014.[35][Level of evidence C2] The following three predefined homologous recombination deficiency subgroups on the basis of tumor mutational analysis were studied: The drug was given orally at 600 mg twice daily, and patients were treated until disease progression or other reasons for discontinuation. Median duration of treatment for the 204 patients was 5.7 months.

The study also showed that variant and methylation status of BRCA and other homologous recombination repair–related genes, such as RAD51C, can be associated with high genomic LOH in BRCA wild-type tumors, conferring higher rates of response to rucaparib than are seen in patients with low genomic LOH.

Rucaparib was later assessed as maintenance therapy after response to platinum therapy in a randomized double-blind, placebo-controlled phase III trial (ARIEL3 [NCT01968213]).[36] To be eligible, patients had high-grade carcinomas that were previously treated with at least two platinum-containing regimens and had achieved complete or partial responses to the last platinum-containing regimen. In a 2:1 treatment allocation, 375 patients received rucaparib, and 189 patients received placebo.

Rucaparib was later assessed as maintenance therapy after response to platinum therapy in a randomized double-blind, placebo-controlled phase III trial (ARIEL3 [NCT01968213]).[36] To be eligible, patients had high-grade carcinomas that were previously treated with at least two platinum-containing regimens and had achieved complete or partial responses to the last platinum-containing regimen. In a 2:1 treatment allocation, 375 patients received rucaparib, and 189 patients received placebo.

PFS, as determined by the investigator, was the primary end point using a step-down procedure for the following three determined, nested treatment cohorts:

Rucaparib was later assessed as maintenance therapy after response to platinum therapy in a randomized double-blind, placebo-controlled phase III trial (ARIEL3 [NCT01968213]).[36] To be eligible, patients had high-grade carcinomas that were previously treated with at least two platinum-containing regimens and had achieved complete or partial responses to the last platinum-containing regimen. In a 2:1 treatment allocation, 375 patients received rucaparib, and 189 patients received placebo. › PFS, as determined by the investigator, was the primary end point using a step-down procedure for the following three determined, nested treatment cohorts:

Patients known to have deleterious germline or somatic BRCA variants: PFS of 16.6 months in the rucaparib group (95% CI, 13.4–22.9) versus 5.4 months in the placebo group (95% CI, 3.4–6.7; HR, 0.23; 95% CI, 0.16–0.34; P < .0001).

Rucaparib was later assessed as maintenance therapy after response to platinum therapy in a randomized double-blind, placebo-controlled phase III trial (ARIEL3 [NCT01968213]).[36] To be eligible, patients had high-grade carcinomas that were previously treated with at least two platinum-containing regimens and had achieved complete or partial responses to the last platinum-containing regimen. In a 2:1 treatment allocation, 375 patients received rucaparib, and 189 patients received placebo. › PFS, as determined by the investigator, was the primary end point using a step-down procedure for the following three determined, nested treatment cohorts:

Patients with homologous recombination deficiencies: PFS of 13.6 months in the rucaparib group (95% CI, 10.9–16.2) versus 5.4 months in the placebo group (95% CI, 5.1–5.6; HR, 0.32; 95% CI, 0.24–0.42; P < .00011).

Rucaparib was later assessed as maintenance therapy after response to platinum therapy in a randomized double-blind, placebo-controlled phase III trial (ARIEL3 [NCT01968213]).[36] To be eligible, patients had high-grade carcinomas that were previously treated with at least two platinum-containing regimens and had achieved complete or partial responses to the last platinum-containing regimen. In a 2:1 treatment allocation, 375 patients received rucaparib, and 189 patients received placebo. › PFS, as determined by the investigator, was the primary end point using a step-down procedure for the following three determined, nested treatment cohorts:

The intention-to-treat population: PFS of 10.8 months in the rucaparib group (95% CI, 8.3–11.4) versus 5.4 months in the placebo group (95% CI, 5.3–5.5; HR, 0.24–0.42; P < .0001.

Rucaparib was later assessed as maintenance therapy after response to platinum therapy in a randomized double-blind, placebo-controlled phase III trial (ARIEL3 [NCT01968213]).[36] To be eligible, patients had high-grade carcinomas that were previously treated with at least two platinum-containing regimens and had achieved complete or partial responses to the last platinum-containing regimen. In a 2:1 treatment allocation, 375 patients received rucaparib, and 189 patients received placebo.

Treatment-emergent adverse events of grade 3 or higher in the rucaparib group versus the placebo group consisted primarily of anemia (19% vs. 1%) and increased alanine aminotransferase or aspartate aminotransferase (10% vs. 0%).

Rucaparib was later assessed as maintenance therapy after response to platinum therapy in a randomized double-blind, placebo-controlled phase III trial (ARIEL3 [NCT01968213]).[36] To be eligible, patients had high-grade carcinomas that were previously treated with at least two platinum-containing regimens and had achieved complete or partial responses to the last platinum-containing regimen. In a 2:1 treatment allocation, 375 patients received rucaparib, and 189 patients received placebo.

In an updated outcomes, intention-to-treat, and safety analysis for all cohorts, at a median follow-up of 28 months, rucaparib had significant persistent advantages in PFS compared with placebo (14.3 months vs. 8.8 months [HR, 0.43; 95% CI, 0,35−0.53]).[37][Level of evidence B1]

Rucaparib was later assessed as maintenance therapy after response to platinum therapy in a randomized double-blind, placebo-controlled phase III trial (ARIEL3 [NCT01968213]).[36] To be eligible, patients had high-grade carcinomas that were previously treated with at least two platinum-containing regimens and had achieved complete or partial responses to the last platinum-containing regimen. In a 2:1 treatment allocation, 375 patients received rucaparib, and 189 patients received placebo.

Time to first subsequent therapy, time to progression on subsequent therapy, and time to start a second subsequent treatment were also significantly in favor of rucaparib.

Rucaparib was later assessed as maintenance therapy after response to platinum therapy in a randomized double-blind, placebo-controlled phase III trial (ARIEL3 [NCT01968213]).[36] To be eligible, patients had high-grade carcinomas that were previously treated with at least two platinum-containing regimens and had achieved complete or partial responses to the last platinum-containing regimen. In a 2:1 treatment allocation, 375 patients received rucaparib, and 189 patients received placebo.

Three occurrences of AML/myelodysplasia treatment-related events had been previously reported, and treatment-emergent serious adverse events were recorded in 22% of patients who received rucaparib versus 11% of patients who received placebo.

Rucaparib was later assessed as maintenance therapy after response to platinum therapy in a randomized double-blind, placebo-controlled phase III trial (ARIEL3 [NCT01968213]).[36] To be eligible, patients had high-grade carcinomas that were previously treated with at least two platinum-containing regimens and had achieved complete or partial responses to the last platinum-containing regimen. In a 2:1 treatment allocation, 375 patients received rucaparib, and 189 patients received placebo.

Anemia was the most common toxicity attributed to rucaparib (in 22% of patients).

Rucaparib was later assessed as maintenance therapy after response to platinum therapy in a randomized double-blind, placebo-controlled phase III trial (ARIEL3 [NCT01968213]).[36] To be eligible, patients had high-grade carcinomas that were previously treated with at least two platinum-containing regimens and had achieved complete or partial responses to the last platinum-containing regimen. In a 2:1 treatment allocation, 375 patients received rucaparib, and 189 patients received placebo.

In an analysis from this trial of quality-adjusted PFS and quality-adjusted time without symptoms or toxicity, both determinations confirmed that rucaparib was beneficial compared with placebo in all predefined cohorts.[38]

The ARIEL4 trial (NCT02855944) evaluated rucaparib versus chemotherapy in patients with high-grade ovarian epithelial cancer and BRCA variants who had been treated with at least two previous lines of chemotherapy.[39]

The ARIEL4 trial (NCT02855944) evaluated rucaparib versus chemotherapy in patients with high-grade ovarian epithelial cancer and BRCA variants who had been treated with at least two previous lines of chemotherapy.[39]

In the intent-to-treat population, the median OS was 19.4 months in the rucaparib group and 25.4 months in the chemotherapy group (HR, 1.31; 95% CI, 1.00–1.73; P = .0507).

The ARIEL4 trial (NCT02855944) evaluated rucaparib versus chemotherapy in patients with high-grade ovarian epithelial cancer and BRCA variants who had been treated with at least two previous lines of chemotherapy.[39]

In 2022, Clovis Oncology withdrew the indication for rucaparib monotherapy for the treatment of patients with BRCA-altered cancer who had been treated with at least two previous lines of chemotherapy.

QUADRA (NCT02354586) was a multicenter, open-label, single-arm phase II trial that studied niraparib as late-line treatment for patients with ovarian cancer.[40] It enrolled 463 women who had received a median of four (range, 3−5) previous regimens (151 patients were platinum resistant and 161 patients were platinum refractory).

QUADRA (NCT02354586) was a multicenter, open-label, single-arm phase II trial that studied niraparib as late-line treatment for patients with ovarian cancer.[40] It enrolled 463 women who had received a median of four (range, 3−5) previous regimens (151 patients were platinum resistant and 161 patients were platinum refractory).

In the primary efficacy measurable population, 13 of 47 patients responded according to RECIST.[40][Level of evidence C2]

QUADRA (NCT02354586) was a multicenter, open-label, single-arm phase II trial that studied niraparib as late-line treatment for patients with ovarian cancer.[40] It enrolled 463 women who had received a median of four (range, 3−5) previous regimens (151 patients were platinum resistant and 161 patients were platinum refractory).

Homologous recombination deficiency was a predictor of response.

QUADRA (NCT02354586) was a multicenter, open-label, single-arm phase II trial that studied niraparib as late-line treatment for patients with ovarian cancer.[40] It enrolled 463 women who had received a median of four (range, 3−5) previous regimens (151 patients were platinum resistant and 161 patients were platinum refractory).

Because the makers of olaparib and rucaparib found decreased survival in patients who had received previous chemotherapy when a PARP inhibitor was used as monotherapy, in 2022, GSK withdrew the indication for niraparib as monotherapy for fourth-line treatment in patients with ovarian epithelial tumors associated with homologous recombination deficiency.[41]

Niraparib was evaluated further in a double-blind, placebo-controlled phase III trial of 533 patients with platinum-sensitive, predominantly high-grade serous ovarian cancer, who were randomly assigned in a 2:1 ratio to maintenance with oral niraparib or placebo and followed for the primary end point of PFS.[42] Patients were categorized according to the presence or absence of germline BRCA or non-BRCA homologous recombination deficiency–positive ovarian cancer or non-BRCA homologous recombination deficiency–negative ovarian cancer, based on BRCA Analysis testing (Myriad Genetics) from tumor and blood samples.

Niraparib was evaluated further in a double-blind, placebo-controlled phase III trial of 533 patients with platinum-sensitive, predominantly high-grade serous ovarian cancer, who were randomly assigned in a 2:1 ratio to maintenance with oral niraparib or placebo and followed for the primary end point of PFS.[42] Patients were categorized according to the presence or absence of germline BRCA or non-BRCA homologous recombination deficiency–positive ovarian cancer or non-BRCA homologous recombination deficiency–negative ovarian cancer, based on BRCA Analysis testing (Myriad Genetics) from tumor and blood samples.

Patients who received niraparib had significantly longer median PFS duration compared with a placebo.[42][Level of evidence B1] Comparisons across categories ranged from HR, 0.27 for germline BRCA cancer (21.0 months vs. 5.5 months), HR, 0.38 for non-BRCA cancer, homologous recombination deficiency-positive cancer (12.9 months vs. 3.8 months), and HR, 0.45 for non-BRCA, homologous recombination deficiency–negative cancer (9.3 months vs. 3.9 months).

Niraparib was evaluated further in a double-blind, placebo-controlled phase III trial of 533 patients with platinum-sensitive, predominantly high-grade serous ovarian cancer, who were randomly assigned in a 2:1 ratio to maintenance with oral niraparib or placebo and followed for the primary end point of PFS.[42] Patients were categorized according to the presence or absence of germline BRCA or non-BRCA homologous recombination deficiency–positive ovarian cancer or non-BRCA homologous recombination deficiency–negative ovarian cancer, based on BRCA Analysis testing (Myriad Genetics) from tumor and blood samples.

A total of 16.1% of patients who received niraparib and 19.3% of patients who received placebo died during the study.

Niraparib was evaluated further in a double-blind, placebo-controlled phase III trial of 533 patients with platinum-sensitive, predominantly high-grade serous ovarian cancer, who were randomly assigned in a 2:1 ratio to maintenance with oral niraparib or placebo and followed for the primary end point of PFS.[42] Patients were categorized according to the presence or absence of germline BRCA or non-BRCA homologous recombination deficiency–positive ovarian cancer or non-BRCA homologous recombination deficiency–negative ovarian cancer, based on BRCA Analysis testing (Myriad Genetics) from tumor and blood samples.

One-third to nearly one-half of the patients had received at least three previous lines of therapy that included:

Niraparib was evaluated further in a double-blind, placebo-controlled phase III trial of 533 patients with platinum-sensitive, predominantly high-grade serous ovarian cancer, who were randomly assigned in a 2:1 ratio to maintenance with oral niraparib or placebo and followed for the primary end point of PFS.[42] Patients were categorized according to the presence or absence of germline BRCA or non-BRCA homologous recombination deficiency–positive ovarian cancer or non-BRCA homologous recombination deficiency–negative ovarian cancer, based on BRCA Analysis testing (Myriad Genetics) from tumor and blood samples. › One-third to nearly one-half of the patients had received at least three previous lines of therapy that included:

Grade 3 or 4 adverse events that were managed with dose modifications while patients received niraparib included thrombocytopenia (in 33.8% of patients), anemia (in 25.3%), and neutropenia (in 19.6%).

Niraparib was evaluated further in a double-blind, placebo-controlled phase III trial of 533 patients with platinum-sensitive, predominantly high-grade serous ovarian cancer, who were randomly assigned in a 2:1 ratio to maintenance with oral niraparib or placebo and followed for the primary end point of PFS.[42] Patients were categorized according to the presence or absence of germline BRCA or non-BRCA homologous recombination deficiency–positive ovarian cancer or non-BRCA homologous recombination deficiency–negative ovarian cancer, based on BRCA Analysis testing (Myriad Genetics) from tumor and blood samples. › One-third to nearly one-half of the patients had received at least three previous lines of therapy that included:

Other excess severe toxicities in patients who received niraparib occurred at starting doses of 300 mg once daily and included fatigue (in 30 patients vs. 1 patient on the placebo), hypertension (in 30 patients vs. 4 on the placebo), nausea (in 11 patients vs. 2 on the placebo), and vomiting (in 7 patients vs. 1 on the placebo).

Niraparib was evaluated further in a double-blind, placebo-controlled phase III trial of 533 patients with platinum-sensitive, predominantly high-grade serous ovarian cancer, who were randomly assigned in a 2:1 ratio to maintenance with oral niraparib or placebo and followed for the primary end point of PFS.[42] Patients were categorized according to the presence or absence of germline BRCA or non-BRCA homologous recombination deficiency–positive ovarian cancer or non-BRCA homologous recombination deficiency–negative ovarian cancer, based on BRCA Analysis testing (Myriad Genetics) from tumor and blood samples. › One-third to nearly one-half of the patients had received at least three previous lines of therapy that included:

A subsequent analysis of the ENGOT-OV16/NOVA trial (NCT01847274) updates PFS after maintenance niraparib or placebo according to the best response (partial response [PR] or complete response [CR]) from the last platinum-based chemotherapy in patients with germline BRCA variants and in non-germline BRCA variant cohorts.[43]

Niraparib was evaluated further in a double-blind, placebo-controlled phase III trial of 533 patients with platinum-sensitive, predominantly high-grade serous ovarian cancer, who were randomly assigned in a 2:1 ratio to maintenance with oral niraparib or placebo and followed for the primary end point of PFS.[42] Patients were categorized according to the presence or absence of germline BRCA or non-BRCA homologous recombination deficiency–positive ovarian cancer or non-BRCA homologous recombination deficiency–negative ovarian cancer, based on BRCA Analysis testing (Myriad Genetics) from tumor and blood samples. › One-third to nearly one-half of the patients had received at least three previous lines of therapy that included: › A subsequent analysis of the ENGOT-OV16/NOVA trial (NCT01847274) updates PFS after maintenance niraparib or placebo according to the best response (partial response [PR] or complete response [CR]) from the last platinum-based chemotherapy in patients with germline BRCA variants and in non-germline BRCA variant cohorts.[43]

The HR was significant for niraparib versus placebo, and the effect was seen in both cohorts.

Niraparib was evaluated further in a double-blind, placebo-controlled phase III trial of 533 patients with platinum-sensitive, predominantly high-grade serous ovarian cancer, who were randomly assigned in a 2:1 ratio to maintenance with oral niraparib or placebo and followed for the primary end point of PFS.[42] Patients were categorized according to the presence or absence of germline BRCA or non-BRCA homologous recombination deficiency–positive ovarian cancer or non-BRCA homologous recombination deficiency–negative ovarian cancer, based on BRCA Analysis testing (Myriad Genetics) from tumor and blood samples. › One-third to nearly one-half of the patients had received at least three previous lines of therapy that included: › A subsequent analysis of the ENGOT-OV16/NOVA trial (NCT01847274) updates PFS after maintenance niraparib or placebo according to the best response (partial response [PR] or complete response [CR]) from the last platinum-based chemotherapy in patients with germline BRCA variants and in non-germline BRCA variant cohorts.[43]

No meaningful differences in patient-reported outcomes were observed.

Niraparib was evaluated further in a double-blind, placebo-controlled phase III trial of 533 patients with platinum-sensitive, predominantly high-grade serous ovarian cancer, who were randomly assigned in a 2:1 ratio to maintenance with oral niraparib or placebo and followed for the primary end point of PFS.[42] Patients were categorized according to the presence or absence of germline BRCA or non-BRCA homologous recombination deficiency–positive ovarian cancer or non-BRCA homologous recombination deficiency–negative ovarian cancer, based on BRCA Analysis testing (Myriad Genetics) from tumor and blood samples.

A phase III, randomized, double-blind, placebo-controlled study of niraparib maintenance in patients with homologous recombination deficiency–positive advanced ovarian cancer following response to front-line platinum-based chemotherapy (NCT01847274) is closed to patient accrual and results are pending.

Niraparib was evaluated further in a double-blind, placebo-controlled phase III trial of 533 patients with platinum-sensitive, predominantly high-grade serous ovarian cancer, who were randomly assigned in a 2:1 ratio to maintenance with oral niraparib or placebo and followed for the primary end point of PFS.[42] Patients were categorized according to the presence or absence of germline BRCA or non-BRCA homologous recombination deficiency–positive ovarian cancer or non-BRCA homologous recombination deficiency–negative ovarian cancer, based on BRCA Analysis testing (Myriad Genetics) from tumor and blood samples.

Other PARP inhibitor trials have been exploring their role in platinum-resistant disease and their role in combination with other agents.

Olaparib was also evaluated as a single agent in a multicenter phase II trial for patients with documented germline BRCA1 or BRCA2 variants.[44][Level of evidence C3] This trial was open to patients with platinum-resistant ovarian cancer, breast cancer treated with three or more previous regimens, pancreatic cancer with previously administered gemcitabine, or prostate cancer previously treated with hormonal therapy and one systemic therapy. Olaparib was given at 400 mg twice a day. The primary end point was response rate. A total of 298 patients were included. The data from this trial were used by the U.S. Food and Drug Administration (FDA) to approve olaparib for patients with ovarian cancer who have known BRCA1 or BRCA2 variants and have failed three previous regimens.

Olaparib was also evaluated as a single agent in a multicenter phase II trial for patients with documented germline BRCA1 or BRCA2 variants.[44][Level of evidence C3] This trial was open to patients with platinum-resistant ovarian cancer, breast cancer treated with three or more previous regimens, pancreatic cancer with previously administered gemcitabine, or prostate cancer previously treated with hormonal therapy and one systemic therapy. Olaparib was given at 400 mg twice a day. The primary end point was response rate. A total of 298 patients were included. The data from this trial were used by the U.S. Food and Drug Administration (FDA) to approve olaparib for patients with ovarian cancer who have known BRCA1 or BRCA2 variants and have failed three previous regimens.

The overall response rate was 26.2%; the response rate was 31.1% in patients with ovarian cancer.[44][Level of evidence C3]

Several other trials have combined olaparib with either cytotoxic chemotherapy or other biological therapy.[45,46]

Several other trials have combined olaparib with either cytotoxic chemotherapy or other biological therapy.[45,46]

Extension in PFS, but not in OS, has been noted.