Surgery before or after platinum-based chemotherapy and the addition of poly (ADP-ribose) polymerase (PARP) inhibitors to induction and/or consolidation therapy

A double-blind phase III trial (SOLO-1) (NCT01844986) compared maintenance olaparib (300 mg tablets bid) with a placebo. Enrolled patients had newly diagnosed, high-grade serous or endometrioid advanced ovarian cancer with variants of BRCA1, BRCA2, or both, who had a complete or partial clinical response after platinum-based chemotherapy.[56] The study of 391 randomly assigned patients ran from 2013 to 2015. Of those patients, 260 were assigned to receive olaparib, and 131 patients were assigned to receive a placebo. All but three patients had germline pathogenic variants in BRCA1 (n = 191) or BRCA2 (n = 66). The analysis of the primary end point was stopped after 2 years if there was no evidence of disease or was continued until investigator-assessed disease progression. Patients with partial responses at 2 years were permitted to receive the intervention in a blinded manner. Crossover was not specified, but after discontinuation, patients could receive treatments at the discretion of the investigator. The primary end point was PFS, which was defined as from the time of randomization to objective disease progression on imaging (q 12 weeks up to 3 years), or death from any cause.

A double-blind phase III trial (SOLO-1) (NCT01844986) compared maintenance olaparib (300 mg tablets bid) with a placebo. Enrolled patients had newly diagnosed, high-grade serous or endometrioid advanced ovarian cancer with variants of BRCA1, BRCA2, or both, who had a complete or partial clinical response after platinum-based chemotherapy.[56] The study of 391 randomly assigned patients ran from 2013 to 2015. Of those patients, 260 were assigned to receive olaparib, and 131 patients were assigned to receive a placebo. All but three patients had germline pathogenic variants in BRCA1 (n = 191) or BRCA2 (n = 66). The analysis of the primary end point was stopped after 2 years if there was no evidence of disease or was continued until investigator-assessed disease progression. Patients with partial responses at 2 years were permitted to receive the intervention in a blinded manner. Crossover was not specified, but after discontinuation, patients could receive treatments at the discretion of the investigator. The primary end point was PFS, which was defined as from the time of randomization to objective disease progression on imaging (q 12 weeks up to 3 years), or death from any cause.

After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with a placebo (Kaplan-Meier estimates of PFS at 3 years, 60% vs. 27%; HR, 0.3; 95% CI, 0.23–0.41; P < .001).

A double-blind phase III trial (SOLO-1) (NCT01844986) compared maintenance olaparib (300 mg tablets bid) with a placebo. Enrolled patients had newly diagnosed, high-grade serous or endometrioid advanced ovarian cancer with variants of BRCA1, BRCA2, or both, who had a complete or partial clinical response after platinum-based chemotherapy.[56] The study of 391 randomly assigned patients ran from 2013 to 2015. Of those patients, 260 were assigned to receive olaparib, and 131 patients were assigned to receive a placebo. All but three patients had germline pathogenic variants in BRCA1 (n = 191) or BRCA2 (n = 66). The analysis of the primary end point was stopped after 2 years if there was no evidence of disease or was continued until investigator-assessed disease progression. Patients with partial responses at 2 years were permitted to receive the intervention in a blinded manner. Crossover was not specified, but after discontinuation, patients could receive treatments at the discretion of the investigator. The primary end point was PFS, which was defined as from the time of randomization to objective disease progression on imaging (q 12 weeks up to 3 years), or death from any cause.

Grades 3 and 4 adverse events were present in 39% of the patients who received olaparib versus 18% who received a placebo. The most common events with olaparib were fatigue, vomiting, and anemia. Drug discontinuation occurred in 12% of the patients who received olaparib versus 2% who received a placebo.

A double-blind phase III trial (SOLO-1) (NCT01844986) compared maintenance olaparib (300 mg tablets bid) with a placebo. Enrolled patients had newly diagnosed, high-grade serous or endometrioid advanced ovarian cancer with variants of BRCA1, BRCA2, or both, who had a complete or partial clinical response after platinum-based chemotherapy.[56] The study of 391 randomly assigned patients ran from 2013 to 2015. Of those patients, 260 were assigned to receive olaparib, and 131 patients were assigned to receive a placebo. All but three patients had germline pathogenic variants in BRCA1 (n = 191) or BRCA2 (n = 66). The analysis of the primary end point was stopped after 2 years if there was no evidence of disease or was continued until investigator-assessed disease progression. Patients with partial responses at 2 years were permitted to receive the intervention in a blinded manner. Crossover was not specified, but after discontinuation, patients could receive treatments at the discretion of the investigator. The primary end point was PFS, which was defined as from the time of randomization to objective disease progression on imaging (q 12 weeks up to 3 years), or death from any cause.

No significant changes in quality of life occurred in either group.[56][Level of evidence B1]

A double-blind phase III trial (SOLO-1) (NCT01844986) compared maintenance olaparib (300 mg tablets bid) with a placebo. Enrolled patients had newly diagnosed, high-grade serous or endometrioid advanced ovarian cancer with variants of BRCA1, BRCA2, or both, who had a complete or partial clinical response after platinum-based chemotherapy.[56] The study of 391 randomly assigned patients ran from 2013 to 2015. Of those patients, 260 were assigned to receive olaparib, and 131 patients were assigned to receive a placebo. All but three patients had germline pathogenic variants in BRCA1 (n = 191) or BRCA2 (n = 66). The analysis of the primary end point was stopped after 2 years if there was no evidence of disease or was continued until investigator-assessed disease progression. Patients with partial responses at 2 years were permitted to receive the intervention in a blinded manner. Crossover was not specified, but after discontinuation, patients could receive treatments at the discretion of the investigator. The primary end point was PFS, which was defined as from the time of randomization to objective disease progression on imaging (q 12 weeks up to 3 years), or death from any cause.

The results of an updated analysis indicated that the risk of disease progression or death was reduced as follows:[57]

A double-blind phase III trial (SOLO-1) (NCT01844986) compared maintenance olaparib (300 mg tablets bid) with a placebo. Enrolled patients had newly diagnosed, high-grade serous or endometrioid advanced ovarian cancer with variants of BRCA1, BRCA2, or both, who had a complete or partial clinical response after platinum-based chemotherapy.[56] The study of 391 randomly assigned patients ran from 2013 to 2015. Of those patients, 260 were assigned to receive olaparib, and 131 patients were assigned to receive a placebo. All but three patients had germline pathogenic variants in BRCA1 (n = 191) or BRCA2 (n = 66). The analysis of the primary end point was stopped after 2 years if there was no evidence of disease or was continued until investigator-assessed disease progression. Patients with partial responses at 2 years were permitted to receive the intervention in a blinded manner. Crossover was not specified, but after discontinuation, patients could receive treatments at the discretion of the investigator. The primary end point was PFS, which was defined as from the time of randomization to objective disease progression on imaging (q 12 weeks up to 3 years), or death from any cause. › The results of an updated analysis indicated that the risk of disease progression or death was reduced as follows:[57]

By 69% with olaparib (HR, 0.31; 95% CI, 0.21–0.46) compared with 63% with placebo (HR, 0.37; 95% CI, 0.24–0.58) in patients undergoing up-front or interval surgery;

A double-blind phase III trial (SOLO-1) (NCT01844986) compared maintenance olaparib (300 mg tablets bid) with a placebo. Enrolled patients had newly diagnosed, high-grade serous or endometrioid advanced ovarian cancer with variants of BRCA1, BRCA2, or both, who had a complete or partial clinical response after platinum-based chemotherapy.[56] The study of 391 randomly assigned patients ran from 2013 to 2015. Of those patients, 260 were assigned to receive olaparib, and 131 patients were assigned to receive a placebo. All but three patients had germline pathogenic variants in BRCA1 (n = 191) or BRCA2 (n = 66). The analysis of the primary end point was stopped after 2 years if there was no evidence of disease or was continued until investigator-assessed disease progression. Patients with partial responses at 2 years were permitted to receive the intervention in a blinded manner. Crossover was not specified, but after discontinuation, patients could receive treatments at the discretion of the investigator. The primary end point was PFS, which was defined as from the time of randomization to objective disease progression on imaging (q 12 weeks up to 3 years), or death from any cause. › The results of an updated analysis indicated that the risk of disease progression or death was reduced as follows:[57]

By 56% with olaparib (HR, 0.44; 95% CI, 0.25–0.77) compared with 67% with placebo (HR, 0.33; 95% CI, 0.23–0.46) in patients with residual or no residual disease after surgery;

A double-blind phase III trial (SOLO-1) (NCT01844986) compared maintenance olaparib (300 mg tablets bid) with a placebo. Enrolled patients had newly diagnosed, high-grade serous or endometrioid advanced ovarian cancer with variants of BRCA1, BRCA2, or both, who had a complete or partial clinical response after platinum-based chemotherapy.[56] The study of 391 randomly assigned patients ran from 2013 to 2015. Of those patients, 260 were assigned to receive olaparib, and 131 patients were assigned to receive a placebo. All but three patients had germline pathogenic variants in BRCA1 (n = 191) or BRCA2 (n = 66). The analysis of the primary end point was stopped after 2 years if there was no evidence of disease or was continued until investigator-assessed disease progression. Patients with partial responses at 2 years were permitted to receive the intervention in a blinded manner. Crossover was not specified, but after discontinuation, patients could receive treatments at the discretion of the investigator. The primary end point was PFS, which was defined as from the time of randomization to objective disease progression on imaging (q 12 weeks up to 3 years), or death from any cause. › The results of an updated analysis indicated that the risk of disease progression or death was reduced as follows:[57]

By 66% with olaparib (HR, 0.34; 95% CI, 0.24–0.47) compared with 69% with placebo (HR, 0.31; 95% CI, 0.18–0.52) in women with clinical complete response or partial response at baseline; and

A double-blind phase III trial (SOLO-1) (NCT01844986) compared maintenance olaparib (300 mg tablets bid) with a placebo. Enrolled patients had newly diagnosed, high-grade serous or endometrioid advanced ovarian cancer with variants of BRCA1, BRCA2, or both, who had a complete or partial clinical response after platinum-based chemotherapy.[56] The study of 391 randomly assigned patients ran from 2013 to 2015. Of those patients, 260 were assigned to receive olaparib, and 131 patients were assigned to receive a placebo. All but three patients had germline pathogenic variants in BRCA1 (n = 191) or BRCA2 (n = 66). The analysis of the primary end point was stopped after 2 years if there was no evidence of disease or was continued until investigator-assessed disease progression. Patients with partial responses at 2 years were permitted to receive the intervention in a blinded manner. Crossover was not specified, but after discontinuation, patients could receive treatments at the discretion of the investigator. The primary end point was PFS, which was defined as from the time of randomization to objective disease progression on imaging (q 12 weeks up to 3 years), or death from any cause. › The results of an updated analysis indicated that the risk of disease progression or death was reduced as follows:[57]

By 59% with olaparib (HR, 0.41; 95% CI, 0.30–0.56) compared with 80% with placebo (HR, 0.20; 95% CI, 0.10–0.37) in patients with BRCA1 or BRCA2 variants.

A double-blind phase III trial (PRIMA [NCT02655016]) compared maintenance niraparib (300 mg tablets once daily and later amended to 200 mg in women <77 kg and/or baseline platelet count <150,000/µL) versus placebo in patients with high-grade serous ovarian cancer before the last cycle of platinum-based chemotherapy.[58] Homologous recombination deficiency as determined by myChoice (Myriad) was present in 50.9% of patients. In a 2:1 randomization (niraparib, n = 487; placebo, n = 246), patients were assigned for comparison of primary end points of PFS for homologous recombination deficiency (50.9%) and for the overall population.

A double-blind phase III trial (PRIMA [NCT02655016]) compared maintenance niraparib (300 mg tablets once daily and later amended to 200 mg in women <77 kg and/or baseline platelet count <150,000/µL) versus placebo in patients with high-grade serous ovarian cancer before the last cycle of platinum-based chemotherapy.[58] Homologous recombination deficiency as determined by myChoice (Myriad) was present in 50.9% of patients. In a 2:1 randomization (niraparib, n = 487; placebo, n = 246), patients were assigned for comparison of primary end points of PFS for homologous recombination deficiency (50.9%) and for the overall population.

At a median follow-up of 13.8 months, the risk of progression in the homologous recombination deficiency population had an HR of 0.43 (95% CI, 0.31−0.59; P < .001) corresponding to a median PFS of 21.9 months versus 10.4 months favoring the drug compared with the placebo. In the overall population selected for this trial, the HR was 0.62, which corresponded to a median PFS of 13.8 months versus 8.2 months (95% CI, 0.50−0.76; P < .001).

A double-blind phase III trial (PRIMA [NCT02655016]) compared maintenance niraparib (300 mg tablets once daily and later amended to 200 mg in women <77 kg and/or baseline platelet count <150,000/µL) versus placebo in patients with high-grade serous ovarian cancer before the last cycle of platinum-based chemotherapy.[58] Homologous recombination deficiency as determined by myChoice (Myriad) was present in 50.9% of patients. In a 2:1 randomization (niraparib, n = 487; placebo, n = 246), patients were assigned for comparison of primary end points of PFS for homologous recombination deficiency (50.9%) and for the overall population.

Grade 3 or higher adverse events, none fatal, consisted of anemia in 31% of patients, thrombocytopenia in 28.7% of patients, and neutropenia in 12.8% of patients; 58 of 307 discontinuations of niraparib were caused by adverse events versus 5 of 175 discontinuations of the placebo.

VELIA/GOG-3005 (NCT02470585), a phase III placebo-controlled study, assessed the efficacy of oral veliparib added to first-line induction chemotherapy with carboplatin/paclitaxel and continued as maintenance chemotherapy.[59] The study randomly assigned 1,140 patients in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance, chemotherapy plus veliparib followed by placebo maintenance, and chemotherapy plus veliparib induction and maintenance (labeled as ‘veliparib throughout’). Doses of veliparib were 150 mg twice daily during induction, and patients who completed six cycles without progression received single-agent veliparib (or matching placebo) at 300 mg twice daily for 2 weeks (labeled as the transition period), and if no dose-limiting side effects were noted, escalated to 400 mg twice daily for an additional 30 cycles of 3 weeks of oral drug. The study accrued patients from 2015 to 2017, and the data was analyzed at a median follow-up of 28 months. As in the PRIMA study above, efficacy analyses were performed in three sequential inclusive populations: 1) the BRCA variant cohort, 2) the homologous recombination deficiency cohort (that included the preceding cohort), and 3) the intention-to-treat population.

VELIA/GOG-3005 (NCT02470585), a phase III placebo-controlled study, assessed the efficacy of oral veliparib added to first-line induction chemotherapy with carboplatin/paclitaxel and continued as maintenance chemotherapy.[59] The study randomly assigned 1,140 patients in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance, chemotherapy plus veliparib followed by placebo maintenance, and chemotherapy plus veliparib induction and maintenance (labeled as ‘veliparib throughout’). Doses of veliparib were 150 mg twice daily during induction, and patients who completed six cycles without progression received single-agent veliparib (or matching placebo) at 300 mg twice daily for 2 weeks (labeled as the transition period), and if no dose-limiting side effects were noted, escalated to 400 mg twice daily for an additional 30 cycles of 3 weeks of oral drug. The study accrued patients from 2015 to 2017, and the data was analyzed at a median follow-up of 28 months. As in the PRIMA study above, efficacy analyses were performed in three sequential inclusive populations: 1) the BRCA variant cohort, 2) the homologous recombination deficiency cohort (that included the preceding cohort), and 3) the intention-to-treat population.

At a median follow-up of 28 months, the BRCA variant cohort experienced a PFS of 34.7 months with veliparib throughout versus 22.0 months in the chemotherapy-only arm (induction veliparib added without veliparib maintenance was not compared). This corresponded to an HR of 0.44 (95% CI, 0.28−0.68; P < .001).

VELIA/GOG-3005 (NCT02470585), a phase III placebo-controlled study, assessed the efficacy of oral veliparib added to first-line induction chemotherapy with carboplatin/paclitaxel and continued as maintenance chemotherapy.[59] The study randomly assigned 1,140 patients in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance, chemotherapy plus veliparib followed by placebo maintenance, and chemotherapy plus veliparib induction and maintenance (labeled as ‘veliparib throughout’). Doses of veliparib were 150 mg twice daily during induction, and patients who completed six cycles without progression received single-agent veliparib (or matching placebo) at 300 mg twice daily for 2 weeks (labeled as the transition period), and if no dose-limiting side effects were noted, escalated to 400 mg twice daily for an additional 30 cycles of 3 weeks of oral drug. The study accrued patients from 2015 to 2017, and the data was analyzed at a median follow-up of 28 months. As in the PRIMA study above, efficacy analyses were performed in three sequential inclusive populations: 1) the BRCA variant cohort, 2) the homologous recombination deficiency cohort (that included the preceding cohort), and 3) the intention-to-treat population.

For the homologous recombination deficiency population, PFS occurred at a median of 31.9 months for the veliparib throughout arm versus 20.5 months for the chemotherapy-alone arm, with an HR of 0.57 (95% CI, 0.43−0.76; P < .001).

VELIA/GOG-3005 (NCT02470585), a phase III placebo-controlled study, assessed the efficacy of oral veliparib added to first-line induction chemotherapy with carboplatin/paclitaxel and continued as maintenance chemotherapy.[59] The study randomly assigned 1,140 patients in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance, chemotherapy plus veliparib followed by placebo maintenance, and chemotherapy plus veliparib induction and maintenance (labeled as ‘veliparib throughout’). Doses of veliparib were 150 mg twice daily during induction, and patients who completed six cycles without progression received single-agent veliparib (or matching placebo) at 300 mg twice daily for 2 weeks (labeled as the transition period), and if no dose-limiting side effects were noted, escalated to 400 mg twice daily for an additional 30 cycles of 3 weeks of oral drug. The study accrued patients from 2015 to 2017, and the data was analyzed at a median follow-up of 28 months. As in the PRIMA study above, efficacy analyses were performed in three sequential inclusive populations: 1) the BRCA variant cohort, 2) the homologous recombination deficiency cohort (that included the preceding cohort), and 3) the intention-to-treat population.

In the overall population selected, the median PFS was 23.5 months for the veliparib throughout arm versus 17.3 months for the chemotherapy-alone arm, corresponding to an HR of 0.68 (95% CI, 0.56−0.83; P < .001).

VELIA/GOG-3005 (NCT02470585), a phase III placebo-controlled study, assessed the efficacy of oral veliparib added to first-line induction chemotherapy with carboplatin/paclitaxel and continued as maintenance chemotherapy.[59] The study randomly assigned 1,140 patients in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance, chemotherapy plus veliparib followed by placebo maintenance, and chemotherapy plus veliparib induction and maintenance (labeled as ‘veliparib throughout’). Doses of veliparib were 150 mg twice daily during induction, and patients who completed six cycles without progression received single-agent veliparib (or matching placebo) at 300 mg twice daily for 2 weeks (labeled as the transition period), and if no dose-limiting side effects were noted, escalated to 400 mg twice daily for an additional 30 cycles of 3 weeks of oral drug. The study accrued patients from 2015 to 2017, and the data was analyzed at a median follow-up of 28 months. As in the PRIMA study above, efficacy analyses were performed in three sequential inclusive populations: 1) the BRCA variant cohort, 2) the homologous recombination deficiency cohort (that included the preceding cohort), and 3) the intention-to-treat population.

Veliparib contributed to a higher rate of anemia and thrombocytopenia when combined with chemotherapy, and contributed overall to nausea and fatigue. Adverse events unrelated to progression during the maintenance phase led to drug discontinuation in 82 patients. Forty of 377 patients going onto maintenance therapy in the veliparib throughout cohort withdrew consent for the trial drug, 22 patients in the chemotherapy-plus-placebo cohort of 371 patients withdrew consent for the trial drug, and 24 patients in the veliparib only as maintenance (not further analyzed in the comparisons) cohort of 383 patients withdrew consent for the trial drug.

PAOLA1 (NCT02477644), a placebo-controlled trial, compared first-line chemotherapy with carboplatin/paclitaxel followed by bevacizumab maintenance for 2 years, to the inclusion of olaparib versus placebo in the maintenance phase.[60] This study included 537 patients who were assessed for BRCA variants (including somatic variants) and a nonhomologous recombination deficiency cohort.

PAOLA1 (NCT02477644), a placebo-controlled trial, compared first-line chemotherapy with carboplatin/paclitaxel followed by bevacizumab maintenance for 2 years, to the inclusion of olaparib versus placebo in the maintenance phase.[60] This study included 537 patients who were assessed for BRCA variants (including somatic variants) and a nonhomologous recombination deficiency cohort.

PFS in the 29% of patients with BRCA variants was 37.2 months for bevacizumab-plus-olaparib group versus 21.7 months for the bevacizumab-alone maintenance group, which corresponded to an HR of 0.31.

PAOLA1 (NCT02477644), a placebo-controlled trial, compared first-line chemotherapy with carboplatin/paclitaxel followed by bevacizumab maintenance for 2 years, to the inclusion of olaparib versus placebo in the maintenance phase.[60] This study included 537 patients who were assessed for BRCA variants (including somatic variants) and a nonhomologous recombination deficiency cohort.

For the non-BRCA population, the HR was 0.71, which corresponded to a median PFS of 18.9 months versus 16.0 months.

PAOLA1 (NCT02477644), a placebo-controlled trial, compared first-line chemotherapy with carboplatin/paclitaxel followed by bevacizumab maintenance for 2 years, to the inclusion of olaparib versus placebo in the maintenance phase.[60] This study included 537 patients who were assessed for BRCA variants (including somatic variants) and a nonhomologous recombination deficiency cohort.

For the overall population, the HR was 0.59, which corresponded to a PFS of 22.1 months for the bevacizumab-plus-olaparib group versus 16.6 months for the bevacizumab-alone maintenance group.