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The FDA has approved olaparib plus bevacizumab for the maintenance treatment of patients with advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy with bevacizumab.
The FDA has approved the combination of olaparib (Lynparza) and bevacizumab (Avastin) for the maintenance treatment of patients with advanced ovarian cancer who are in complete or partial response (PR) to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)—positive status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability.1
The approval was based on results from the pivotal phase 3 PAOLA-1 trial, in which the combination reduced the risk of disease progression or death compared with bevacizumab alone. The benefit with the addition of olaparib was most pronounced in patients with HRD-positive tumors, including tumors that had BRCA mutations (HR, 0.33; 95% CI, 0.25-0.45). In this subgroup, the median progression-free survival (PFS) was 37.2 months and 17.7 months with the olaparib combination and bevacizumab alone, respectively. In those who had HRD-positive tumors without BRCA mutations, the median PFS was 28.1 months with olaparib/bevacizumab and 16.6 months with bevacizumab alone, respectively (HR, 0.43; 95% CI, 0.28-0.66).
In the ITT population, the combination led to an investigator-assessed 41% reduction in the risk of disease progression or death compared with bevacizumab alone (HR, 0.59; 95% CI, 0.49-0.72; P <.001). Additionally, after a median follow-up of 22.9 months, the median PFS was 22.1 months and 16.6 months with the combination and bevacizumab alone, respectively.
“Ovarian cancer is a devastating disease. The magnitude of benefit in HRD-positive patients in the PAOLA-1 trial is impactful. I look forward to seeing this translate into clinical practice,” Isabelle Ray-Coquard, MD, PhD, principal investigator of the PAOLA-1 trial and medical oncologist, Centre Leon Bérard, Université Claude Bernard, in Lyon, France, stated in a press release.2
In the double-blind, placebo-controlled, phase 3 PAOLA-1 trial, patients with newly diagnosed, advanced, FIGO stage III to IV, high-grade, serous or endometroid ovarian, fallopian tube, or peritoneal cancer who had a complete response (CR) or PR to frontline platinum-based chemotherapy and bevacizumab, regardless of genetic biomarker status or their outcome to prior surgery, were randomized 2:1 to receive olaparib in combination with bevacizumab (n = 537) or bevacizumab with placebo (n = 269) as a first-line maintenance treatment. Bevacizumab was administered at 15 mg/kg every 3 weeks on day 1; in the experimental arm, olaparib was given at 300 mg twice daily.
The primary end point was investigator-assessed PFS; secondary end points included PFS2, overall survival, time until first subsequent therapy or death, and global health status—quality of life dimension of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire.
Regarding safety, the most common adverse events (AEs) occurring in ≥20% of patients in the combination arm versus the bevacizumab-alone arm were fatigue (53% vs 32%, respectively), nausea (53% vs 22%), hypertension (46% vs 60%), anemia (41% vs 10%), lymphopenia (24% vs 9%), vomiting (22% vs 11%), and arthralgia (22% vs 24%).
Grade ≥3 AEs were reported in 57% of patients who received the addition of olaparib to bevacizumab and occurred in 51% of patients on bevacizumab alone. These AEs included hypertension (19% with olaparib/bevacizumab vs 30% with bevacizumab alone), anemia (17% vs <1%, respectively), lymphopenia (7% vs 1%), fatigue (5% vs 1%), neutropenia (6% vs 3%), nausea (2% vs 1%), diarrhea (both 2%), leukopenia (2% vs 1%), vomiting (1% vs 2%), and abdominal pain (1% vs 2%).
AEs that led to dose interruption occurred in 54% of patients on olaparib plus bevacizumab compared with 24% of patients on single-agent bevacizumab. Dose reductions occurred in 41% and 7% of patients on olaparib/bevacizumab and bevacizumab alone, respectively. Treatment discontinuations occurred in 20% of patients on the combination compared with 6% of those on bevacizumab alone.
In December 2018, the FDA approved olaparib as a maintenance treatment for patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in CR or PR to frontline platinum-based chemotherapy.
This approval was based on findings from the phase 3 SOLO-1 trial, in which olaparib reduced the risk of disease progression or death by 70% in patients with BRCA-mutant advanced ovarian cancer who were in CR or PR to platinum-based chemotherapy (HR, 0.30; 95% CI, 0.23-0.41; P <.001) compared with placebo following platinum-based chemotherapy.3
Olaparib is also approved as a single agent for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in CR or PR to platinum-based chemotherapy. The PARP inhibitor is also approved for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with ≥3 prior lines of chemotherapy.
Patients were enrolled regardless of the type or extent of surgery (upfront or interval). The median age was 60.5 years, and all patients had an ECOG performance status of 0 or 1. A total of 95.5% patients had serous histology.