The addition of PARP inhibitors as maintenance therapy to first-line treatment: A new standard of care?
Over recent years, we have witnessed only little improvement in the life expectancy of women with advanced ovarian cancer. Recent studies have shed light on the clinical benefit of using a PARP inhibitor as part of the front-line treatment to further improve the survival prospects of these patients.
Phase III PRIMA/ENGOT-OV26/GOG-3012 was designed to evaluate the efficacy and safety of niraparib in patients with newly diagnosed ovarian cancer and at high risk for recurrence after response to first-line platinum-based chemotherapy.5,7 A total of 733 patients were randomized 2:1 to receive either niraparib (200 mg or 300 mg, depending on the platelet count and body weight) or placebo, once daily for 36 months or until disease progression.
After a median follow-up of 13.8 months, the trial met its primary endpoint. Niraparib therapy after response to platinum-based chemotherapy reduced the risk of progression by 57% in the homologous recombination (HR)-deficient population (HR: 0.43 [95% CI: 0.31−0.59]; p<0.001) and by 38% in the overall population (HR: 0.62 [95% CI: 0.50−0.76]; p<0.001) (Figure 1).5 Consistent with prior studies, niraparib provided significant clinical benefit across biomarker subgroups, including HR-deficient patients with either BRCA wild-type or BRCA mutant ovarian cancer and those with HR-proficient tumors. Generally, the safety profile of niraparib was manageable. The most common grade ≥3 adverse events included anemia (31%), thrombocytopenia (29%), and neutropenia (13%). No fatal events due to treatment-related adverse events were observed in this study.
The phase III PAOLA-1/ENGOT-ov25 trial investigated the combination of olaparib plus bevacizumab as maintenance therapy in patients with advanced ovarian cancer who had complete or partial response to first-line standard-of-care treatment, including surgery, platinum-taxane based chemotherapy and bevacizumab (≥3 cycles). This was a population which was not restricted by the surgical outcome or BRCA mutation status. Patients were randomized 2:1 to receive either 300 mg olaparib twice a day for 2 years plus 15 mg/kg bevacizumab every 3 weeks for a total of 15 months or matching placebo plus bevacizumab at the same dose and schedule.
The addition of olaparib to bevacizumab significantly prolonged investigator-assessed progression-free survival (PFS) (HR: 0.59 [95% CI: 0.49−0.72]; p<0.0001) (Figure 2) and demonstrated a favorable trend across all subgroups included in this analysis. In particular, prespecified subgroup analyses showed that patients with BRCA-mutated tumors and those with a positive homologous recombination deficiency (HRD) status irrespective of the presence of BRCA mutations had the greatest benefit from the maintenance therapy with olaparib plus bevacizumab. The incidence and type of adverse events observed in the olaparib arm were consistent with previous reports. In addition, the combination of olaparib and bevacizumab did not impact the health-related quality of life (HRQoL).
Overall, these 2 trials demonstrated a consistent benefit of using PARP inhibitors as maintenance therapy in first-line treatment of advanced ovarian cancer.8 The greatest magnitude of benefit was observed in the HRD-positive subgroup, highlighting the importance of incorporating companion diagnostic tests to select patients who may benefit the most. Interestingly, among patients with a positive HRD status, those without BRCA mutations were also associated with a significantly improved PFS following maintenance with PARP inhibitor-containing regimens. The hazard ratios in these subgroups ranged between 0.43 in PAOLA-1/ENGOT-ov25 to 0.50 in PRIMA/ENGOT-OV26/GOG-3012. Therefore, these studies suggest that the benefit of this treatment strategy may be extended to a new population of patients with a BRCA wild type status.
Veliparib, in combination with chemotherapy and followed by maintenance, as a first-line treatment strategy in advanced ovarian cancer
VELIA/GOG-3005 is the first phase III trial to assess the impact of combining chemotherapy with a PARP inhibitor as induction therapy as well as maintenance in the first-line treatment of patients with advanced ovarian cancer.6,9 Participants were enrolled irrespective of BRCA status, surgical management or response to therapy.
In this study, a total of 1,140 patients were randomized to one of the following treatment arms: chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout; n=382); chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only; n=383); chemotherapy plus placebo followed by placebo maintenance (control; n=375).6 Chemotherapy consisted of carboplatin plus paclitaxel that was combined with either veliparib or placebo for 6 cycles followed by an additional 30 cycles of veliparib or placebo in the maintenance settings.
After a median follow-up of 28 months, the combination of veliparib and chemotherapy as induction therapy followed by veliparib maintenance significantly prolonged PFS compared with the control regimen in patients with a BRCA mutation (HR: 0.44 [95% CI: 0.28−0.68]; p<0.001) and in the overall intention-to-treat population (HR: 0.68 [95% CI: 0.56−0.83]; p<0.001) (Figure 3).6 In contrast, no clinically meaningful improvement in PFS was observed in HRD-patients with BRCA wild-type or those with proficient disease. In addition, veliparib given only during the chemotherapy cycles (veliparib combination group) did not demonstrate an improvement in PFS compared with the control arm (HR: 1.07 [95% CI: 0.90−1.29]).
Observed toxicities were consistent with the known safety profile of chemotherapy during the combination phase and with that of veliparib during the maintenance phase.6
Taken together, these data support the use of poly(ADP)-ribose polymerase (PARP) inhibitors for the first-line treatment of BRCA-mutated patients and/or with HR-deficiency.4–6,8
In the patient population with a positive homologous recombination deficient (HRD) status, niraparib, olaparib and veliparib provide similar clinical benefits among those harboring BRCA mutations. However, only niraparib monotherapy shows a benefit in PFS in the HR-proficient population, though only in an exploratory analysis.
In patients with HR proficient tumors, the benefit of PARP inhibitors appears to be less pronounced. Their use in this population is currently under discussion.
Overall, all three PARP inhibitors showed a manageable safety profile with no new safety signals.