PARP Inhibitors in Frontline Ovarian Cancer Treatment: A Review of Clinical Trials
核心洞察
Frontline PARP (搜索) inhibitor maintenance shows greatest benefit in patients with BRCA (搜索)-associated ovarian cancers, followed by those with homologous recombination deficient (HRD (搜索)) tumors.
Key factors in deciding on frontline PARP (搜索) inhibitor therapy include FDA indication, dosing preference, toxicity profiles, patient-specific risk-benefit assessment, and cost considerations.
Ongoing trials are exploring PARP (搜索) inhibitor combinations with anti-angiogenics, immunotherapies, and agents targeting PARP inhibitor resistance to further improve outcomes.
The use of poly (ADP-ribose) polymerase (PARP (搜索)) inhibitors in the front-line management of advanced ovarian cancer (搜索) has emerged as a promising strategy to improve patient outcomes. Several phase 3 randomized controlled trials (SOLO1 (搜索), PRIMA (搜索), PAOLA-1 (搜索), and VELIA (搜索)) have evaluated PARP inhibitors in the primary treatment of ovarian cancer, revealing their potential and nuances in efficacy across different patient subgroups. These studies collectively suggest that PARP maintenance in the upfront setting is most beneficial among patients with BRCA (搜索)-associated ovarian cancers, followed by patients with tumors that harbor homologous recombination deficiencies (HRD (搜索)). All three studies that included an all comer population were able to demonstrate benefit of PARP inhibitors regardless of biomarker status.
SOLO1 Trial: Olaparib in BRCA-Mutated Ovarian Cancer
The SOLO1 (搜索) trial, a phase III randomized study, assessed olaparib maintenance in patients with germline or somatic BRCA (搜索) mutations and stage III or IV high-grade serous or endometrioid ovarian cancer (搜索) who responded to first-line platinum-based chemotherapy. Patients were randomized (2:1) to receive olaparib tablets (300mg twice daily) or placebo until progression or toxicity, with treatment potentially continuing beyond 24 months based on clinical benefit. The rate of freedom from disease progression and death at 3 years was 60% in the olaparib group versus 27% in the placebo group (hazard ratio 0.30; 95% CI: 0.23 to 0.41; P<0.001). This significant improvement led to FDA approval of olaparib as first-line maintenance therapy for advanced-stage ovarian cancer with BRCA mutations.
PRIMA Trial: Niraparib in a Broader Patient Population
The PRIMA (搜索) trial included all patients regardless of HRD (搜索) status. This phase III, multicenter, randomized trial assessed maintenance niraparib following primary platinum-based chemotherapy. Patients had stage III or IV high grade serous or endometrioid ovarian cancer (搜索), with a partial or complete response to 6-9 cycles of chemotherapy. Patients were randomized to oral niraparib or placebo for 36 months or until progression of disease. The primary endpoints for this trial were impact of progression free survival on patients with HRD positive tumors and progression free survival in intention to treat. In the HRD group, progression free survival was 21.9 months in patients who received niraparib compared to 10.4 months in the placebo group (hazard ratio 0.43; 95% CI: 0.31 to 0.59; P<0.001). Importantly, progression free survival was improved with niraparib maintenance in all groups of patients. The intention to treat analysis in all comers revealed that progression free survival was improved in all patients who received niraparib compared to placebo (13.8 months versus 8.2 months [Hazard ratio 0.62 (0.50 – 0.76), <0.001].
PAOLA-1 Trial: Olaparib in Combination with Bevacizumab
Different from the previous trials, the PAOLA-1 (搜索) trial investigated the combination of bevacizumab with or without with PARP (搜索) maintenance. PAOLA-1 included patients with stage III-IV high grade serous or endometrioid ovarian cancer (搜索), who underwent primary treatment with platinum-taxane chemotherapy plus bevacizumab and primary or interval tumor debulking surgery. Participants were randomized to receive olaparib (300 mg twice daily) or placebo for 24 months or until disease progression. Median progression free survival was longer in the olaparib group compared to the placebo group in the primary intention to treat analysis (22.1 months versus 16.6 months, hazard ratio 0.59; 95% CI: 0.49 – 0.72, p<0.001). Among patients with BRCA (搜索)-associated ovarian cancers, median progression-free survival was 37.2 months with the addition of olaparib compared to 21.7 months with placebo (hazard ratio 0.31; 95% CI: 0.20–0.47).
VELIA Trial: Veliparib Throughout Chemotherapy and Maintenance
The VELIA (搜索) trial evaluated veliparib in combination with primary chemotherapy, followed by veliparib maintenance. Participants had stage III or IV high grade serous ovarian cancer (搜索) and underwent either primary or interval tumor debulking surgery. They were then randomized to one of 3 arms: veliparib throughout (carboplatin, paclitaxel, and veliparib followed by veliparib maintenance); veliparib-combination only (carboplatin, paclitaxel and veliparib followed by placebo maintenance); or control group (carboplatin, paclitaxel and placebo followed by placebo maintenance). Among patients with BRCA (搜索)-associated tumors, median progression-free survival for the veliparib-throughout arm was 34.7 months compared to 22.0 months for the control group (hazard ratio 0.44, 95% CI: 0.28-0.68, p<0.001). In the HRD (搜索) group, median progression-free survival was also significantly longer in the veliparib-throughout group compared to controls (31.9 months versus 20.5 months, hazard ratio 0.57, 95% CI: 0.43-0.76, p<0.001), and this benefit was retained in the intention to treat analysis (23.5 months versus 17.3 month, hazard ratio 0.68, 95% CI: 0.56 – 0.83, <0.001].
Considerations for Clinical Practice
When deciding on frontline maintenance PARP (搜索) inhibitor therapy, clinicians must consider multiple factors, including FDA indications, dosing preferences, potential toxicities, and the balance of risks and benefits for each patient subgroup (BRCA (搜索)-associated, HRD (搜索), and HR proficient). Olaparib is FDA-approved for BRCA-associated ovarian cancers, while niraparib is approved for all patients. The choice between these agents should be individualized based on patient preferences and known toxicities. Ongoing clinical trials are exploring combination therapies to potentially overcome these mechanisms. PARP inhibitors are being combined with other anti-angiogenic drugs, immunotherapeutic agents, and inhibitors of pathways implicated in PARP inhibitor resistance.