The combination of olaparib and bevacizumab was found to improve progression-free survival outcomes versus bevacizumab alone as a frontline maintenance treatment in patients with newly diagnosed advanced high-grade serous ovarian cancer, regardless of the timing of surgery or residual disease status after surgery.
The combination of olaparib (Lynparza) and bevacizumab (Avastin) was found to improve progression-free survival (PFS) outcomes versus bevacizumab alone as a frontline maintenance treatment in patients with newly diagnosed advanced high-grade serous ovarian cancer, regardless of the timing of surgery or residual disease status after surgery, according to results from an analysis of the phase III PAOLA-1 trial.1
Results, which were scheduled to be presented during the 2020 SGO Annual Meeting, showed that the regimen had the most significant improvement in PFS in patients without residual disease who had complete surgical debulking in the up-front setting (n = 245; HR, 0.47; 95% CI, 0.29-0.75).
Based on the preliminary findings from PAOLA-1, which were presented during the 2019 ESMO Congress, the FDA granted a priority review designation to a supplemental new drug application for the combination of olaparib and bevacizumab for the maintenance treatment of patients with advanced ovarian cancer who are in either complete response (CR) or partial response (PR) to frontline platinum-based chemotherapy with bevacizumab.2 The FDA is expected to make a decision on the application in the second quarter of 2020.
Earlier findings from PAOLA-1 showed that the combination led to an investigator-assessed 41% reduction in the risk of disease progression or death compared with placebo plus bevacizumab in this patient population (HR, 0.59; 95% CI, 0.49-0.72; P <.001).3 Specifically, the median PFS was 22.1 months and 16.6 months with the combination and placebo/bevacizumab, respectively, after a median follow-up of 22.9 months.
The double-blind, placebo-controlled, phase III PAOLA-1 study enrolled patients with newly diagnosed, advanced, FIGO stage III to IV, high-grade, serous or endometroid ovarian, fallopian tube, or peritoneal cancer who achieved a CR or PR to frontline platinum-based chemotherapy and bevacizumab. Patients were randomized 2:1 to receive first-line maintenance treatment with olaparib plus bevacizumab (n = 537) or bevacizumab with placebo (n = 269), stratified by first-line treatment outcome and tumor BRCA mutation status. 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.
Patients were enrolled regardless of the type or extent of surgery (up front or interval). The median age of the participants was 60.5 years, and all patients had an ECOG performance status of 0 or 1. Moreover, 95.5% of patients had serous histology.
The primary end point of the trial 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.
In the most recent PAOLA-1 analysis, 51% and 42% of patients had up-front and interval surgery, respectively. Sixty percent of patients had no residual macroscopic disease after surgery regardless of timing, and 33% had residual macroscopic disease after surgery; 7% of patients did not undergo surgery.
For those who underwent up-front surgery, the investigative regimen led to a 48% reduction in the risk of death compared with placebo/bevacizumab (HR, 0.52; 95% CI, 0.40-0.69). The median PFS was 29.6 versus 18.2 months, respectively. In those who underwent interval surgery, the median PFS was 21.4 months in the olaparib/bevacizumab arm and was 16.7 months in the placebo/bevacizumab arm (HR, 0.66; 95% CI, 0.50-0.87).
For patients with no residual macroscopic disease after cytoreductive surgery, the median PFS was 29.6 months and 19.3 months with olaparib/bevacizumab and placebo/bevacizumab, respectively (HR, 0.54; 95% CI, 0.42-0.71). However, the median PFS was 18.2 months with olaparib/bevacizumab and 12.9 months with placebo/bevacizumab in patients with residual macroscopic disease following surgery (HR, 0.63; 95% CI, 0.47-0.85).
Specifically, for patients who both underwent interval surgery and had no residual disease, the median PFS was 22.1 months versus 17.7 months in the olaparib/bevacizumab and placebo/bevacizumab arms, respectively (HR, 0.61; 95% CI, 0.41-0.91). In patients who underwent interval surgery with residual disease, the median PFS was 18.7 months with olaparib/bevacizumab compared with 12.3 months with placebo/bevacizumab (HR, 0.70; 95% CI, 0.41-1.2).
Moreover, in those who underwent up-front surgery with residual disease, the median PFS with olaparib/bevacizumab was 17.6 months versus 13.0 months with placebo/bevacizumab (HR, 0.74; 95% CI, 0.48-1.15).
When stratified by stage, in patients with stage III ovarian cancer who had up-front surgery and no residual disease (n = 211), the median PFS was not reached with olaparib/bevacizumab and was 24.9 months with placebo/bevacizumab (HR, 0.45; 95% CI, 0.27-0.75). When including patients with stage III disease who had up-front surgery and residual disease, those who received neoadjuvant chemotherapy, and also those with stage IV disease, the median PFS was 22.0 months with the combination and 16.6 months with olaparib/bevacizumab versus placebo/bevacizumab (HR, 0.65; 95% CI, 0.51-0.82).
Previously reported findings of PAOLA-1 also showed that the benefit with olaparib was most pronounced in patients with tumors that were positive for homologous recombination deficiency (HRD), including those with BRCA mutations (HR, 0.33; 95% CI, 0.25-0.45). In this subgroup, the median PFS was 37.2 months with the olaparib regimen and 17.7 months with placebo/bevacizumab.
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).
By blinded independent central review, the median PFS was 26.1 months and 18.3 months with the combination and placebo/bevacizumab, respectively (HR, 0.63; 95% CI, 0.51-0.77; P <.0001).
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 placebo/bevacizumab. 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 placebo/bevacizumab. Dose reductions occurred in 41% and 7% of patients who received olaparib/bevacizumab versus placebo/bevacizumab, respectively. Treatment discontinuations occurred in 20% of patients on the olaparib combination compared with 6% of those on placebo/bevacizumab.
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, as approved by an FDA-approved companion diagnostic assay.
This approval is based on findings from the phase III 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.4
Olaparib is also indicated as a maintenance treatment for 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.