Two studies presented at the European Society for Medical Oncology (ESMO) 2019 Congress showed the efficacy of poly ADP ribose polymerase (PARP) inhibitors in patients with newly diagnosed ovarian cancer.
In the PRIMA/ENGOT-OV26/GOG-3012 study, presented by González Martín et al (Abstract LBA1; also simultaneously published in The New England Journal of Medicine), patients with newly diagnosed advanced disease who were treated with niraparib after achieving a response to first-line platinum-based chemotherapy had a reduced risk of disease recurrence or death compared to similar patients receiving placebo.
In PAOLA-1/ENGOT-ov25, presented by Ray-Coquard et al (Abstract LBA2), patients with newly diagnosed disease demonstrated improved progression-free survival with the addition of olaparib to bevacizumab maintenance treatment vs bevacizumab alone following platinum-based first-line chemotherapy.
PRIMA/ENGOT-OV26/GOG-3012
Lead author of PRIMA/ENGOT-OV26/GOG-3012 Antonio González Martín, MD, PhD, of Grupo Español de Investigación en Cáncer de Ovario (GEICO) & Clinica Universidad de Navarra, explained that this study was prompted by earlier reports that niraparib improves progression-free survival in patients with recurrent ovarian cancer when administered after platinum-based chemotherapy. Niraparib has shown activity in tumors with germline BRCA mutation, in those with wild-type BRCA, and in tumors harboring homologous recombination deficiency (HRD); thus, patients were enrolled regardless of BRCA status.
Dr. González Martín and colleagues conducted this double-blind, placebo-controlled phase III of niraparib in patients who had been newly diagnosed with advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer. Eligible patients had achieved a complete or partial response to first-line platinum-based chemotherapy. Stratification factors included best response to the first-line chemotherapy, receipt of neoadjuvant chemotherapy, and HRD status per the myChoice HRD test.
Patients were randomly assigned to receive 300 mg of oral niraparib or placebo once daily. Of the 487 patients randomly assigned to niraparib and the 246 assigned to placebo, 247 and 126 patients in the respective treatment arms were HRD-positive. Neoadjuvant chemotherapy had been administered to 67% of the patients, and 31% had achieved partial response following first-line chemotherapy. About 35% of patients had stage IV disease.
The primary endpoint was progression-free survival by blinded independent central review as analyzed using a stratified Cox proportional hazards model and hierarchically tested in HRD-positive patients and the overall population thereafter.
“Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency.”— González Martín et al
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Results
Patients in the overall population treated with niraparib demonstrated improvement in progression-free survival compared to patients on placebo that was even greater in the HRD-positive subgroup. Median progression-free survival in the overall population was 13.8 months (95% confidence interval [CI] = 11.5–14.9) with niraparib compared to 8.2 months (95% CI = 7.3–8.5) with placebo (hazard ratio [HR] = 0.62, 95% CI = 0.5–0.75; P < .0001).
In the HRD-positive subgroup, median progression-free survival was 21.9 months (95% CI = 19.3–not reached) vs 10.4 months (95% CI = 8.1–12.1), with a hazard ratio of 0.43 (95% CI = 0.31–0.59; P < .0001).
The most commonly reported grade ≥ 3 adverse events were anemia in 31% of patients, thrombocytopenia in 29%, and neutropenia in 13% of patients overall. No treatment-related deaths occurred.
The study authors concluded, “Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency.”
PAOLA-1/ENGOT-ov25
Isabelle L. Ray-Coquard, MD, PhD
Isabelle L. Ray-Coquard, MD, PhD, of Centre Léon Bérard presented these trial findings, which evaluated the efficacy and safety of olaparib in tablet formulation plus bevacizumab vs bevacizumab alone in patients with newly diagnosed advanced ovarian cancer. PAOLA-1/ENGOT-ov25 was a randomized, double-blind, international phase III trial that enrolled patients with newly diagnosed, International Federation of Gynecology and Obstetrics stage III to IV, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer.
Patients in clinical complete or partial response following platinum-based chemotherapy plus bevacizumab were randomly assigned 2:1 to receive oral olaparib at 300 mg twice daily for up to 24 months or placebo plus bevacizumab at 15 mg/kg on day 1 every 3 weeks for 15 months, which included doses received during chemotherapy. The patients were stratified by first-line treatment outcome and somatic BRCA mutation status.
The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intent-to-treat population. The median follow-up was 24.0 months for 537 patients in the olaparib/bevacizumab arm and 22.7 months for 269 patients/bevacizumab in the placebo arm.
Analysis of the data at 59% maturity demonstrated a median progression-free survival of 22.1 months with olaparib/bevacizumab vs 16.6 months with placebo/bevacizumab (hazard ratio [HR] 0.59, 95% confidence interval [CI] = 0.49–0.72; P < .0001).
Among patients with a BRCA mutation, median progression-free survival for patients treated with olaparib/bevacizumab was 37.2 months vs 21.7 months with placebo/bevacizumab (HR = 0.31, 95% CI = 0.20–0.47). Patients without a BRCA mutation demonstrated a median progression-free survival of 18.9 months with olaparib/bevacizumab vs 16.0 months with placebo/bevacizumab (HR = 0.71, 95% CI = 0.58–0.88).
Analysis according to HRD status showed that 387 patients were HRD-positive. Of these patients, 152 did not have a BRCA mutation. In HRD-positive patients, the median progression-free survival with olaparib/bevacizumab was 37.2 months vs 17.7 months with placebo/bevacizumab (HR = 0.33, 95% CI = 0.25–0.45). Median progression-free survival in HRD-positive patients without a BRCA mutation treated with olaparib/bevacizumab was 28.1 months vs 16.6 months with placebo/bevacizumab (HR = 0.43, 95% CI = 0.28–0.66). In patients with negative or unknown HRD status treated with olaparib, median progression-free survival was 16.9 months vs 16.0 months with placebo (HR = 0.92, 95% CI = 0.72–1.17).
Time to second progression data were not mature at the time of this analysis.
"Addition of olaparib to bevacizumab maintenance therapy following first-line chemotherapy plus bevacizumab led to a statistically significant and clinically meaningful progression-free survival benefit in patients with advanced ovarian cancer. The progression-free survival benefit in patients with a tumor [somatic] BRCA mutation and in HRD-positive patients was substantial.”— Ray-Coquard et al
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Grade ≥ 3 adverse events occurred in 57% vs 51% of patients receiving olaparib/bevacizumab and placebo/bevacizumab, respectively. The most commonly reported adverse events were hypertension (19% vs 30%) and anemia (17% vs < 1%). There were five fatal treatment-emergent adverse events—one in the olaparib arm and four in the placebo arm. Dose interruptions occurred in 54% vs 24%, dose reductions occurred in 41% vs 7%, and treatment discontinuation occurred in 20% vs 6% of patients receiving olaparib/bevacizumab and placebo/bevacizumab, respectively.
Although treatment interruptions, reductions, and discontinuations occurred more often in patients treated in the olaparib arm, no clinically meaningful difference in health-related quality of life was observed between treatment arms.
The authors concluded, “Addition of olaparib to bevacizumab maintenance therapy following first-line chemotherapy plus bevacizumab led to a statistically significant and clinically meaningful progression-free survival benefit in patients with advanced ovarian cancer. The progression-free survival benefit in patients with a tumor [somatic] BRCA mutation and in HRD-positive patients was substantial.”
Disclosure: PRIMA/ENGOT-OV26/GOG-3012 was funded by Tesaro; PAOLA-1/ENGOT-ov25 was funded by RCAGY Research, AstraZeneca, Merck & Co, Inc, and Hoffmann-La Roche Ltd. For full disclosures of the study authors, visit esmo.org.
