The European Union has approved olaparib in combination with bevacizumab for use as a first-line maintenance treatment in patients with homologous recombination deficient–positive advanced ovarian cancer.
The European Union (EU) has approved olaparib (Lynparza) in combination with bevacizumab (Avastin) for use as a first-line maintenance treatment in patients with homologous recombination deficient (HRD)–positive advanced ovarian cancer, according to an announcement from AstraZeneca.1
The regulatory decision was based on findings from a biomarker subgroup analysis of the phase 3 PAOLA-1 trial (NCT02377644), which showed that the doublet significantly improved progression-free survival (PFS) in patients with advanced serous or endometroid ovarian, fallopian tube, or peritoneal cancer compared with bevacizumab alone.
The PFS benefit with the combination was most pronounced in participants whose tumors had HRD positivity, including those who had BRCA mutations (HR, 0.33; 95% CI, 0.25-0.45). The median PFS in this subset of patients was 37.2 months with the olaparib combination versus 17.7 months with bevacizumab monotherapy.2,3 The median PFS in patients with HRD-positive tumors who did not have BRCA mutations was 28.1 months with the doublet versus 16.6 months with the monotherapy (HR, 0.43; 95% CI, 0.28-0.66).
In the intent-to-treat population, the olaparib combination also reduced the risk of disease progression or death by 41% versus bevacizumab alone, per investigator assessment (HR, 0.59; 95% CI, 0.49-0.72; P <.001). Moreover, at a median follow-up of 22.9 months, the median PFS in the combination and monotherapy arms was 22.1 months and 16.6 months, respectively.
"For women with advanced ovarian cancer, the goal of first-line treatment is to delay disease progression for as long as possible with the intent of achieving long-term remission. Unfortunately, once a patient’s cancer recurs, it historically has been incurable," Isabelle Ray-Coquard, MD, PhD, principal investigator of PAOLA-1, medical oncologist at the Centre Léon Bérard, and president of the GINECO group, stated in a press release. "[Olaparib] together with bevacizumab has demonstrated an impressive median PFS benefit of more than 3 years and is poised to become the standard of care for eligible patients with HRD-positive tumors in the EU.”
The double-blind, placebo-controlled, phase 3 trial enrolled patients with newly diagnosed, FIGO stage III to IV, high-grade, serous or endometroid ovarian, fallopian tube, or peritoneal cancer who achieved a complete response (CR) or partial response to first-line platinum-based chemotherapy plus bevacizumab, irrespective of genetic biomarker status or their outcome before surgery.
Participants were randomized in a 2:1 fashion; 537 patients received maintenance olaparib plus bevacizumab, while 269 patients received maintenance bevacizumab plus placebo. Bevacizumab was given at a dose of 15 mg/kg every 3 weeks on day 1. Olaparib was given at a dose of 300 mg twice daily.
The primary objective of the trial was investigator-assessed PFS, while key secondary end points comprised 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.
With regard to safety, the most frequently reported toxicities with the combination versus the monotherapy included 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 toxicities were experienced by 57% of those on the combination versus 51% of those on the monotherapy. These patients reported hypertension (19%, combination vs 30%, monotherapy), anemia (17% vs <1%, respectively), lymphopenia (7% vs 1%), fatigue (5% vs 1%), neutropenia (6% vs 3%), nausea (2% vs 1%), diarrhea (2% vs 2%), leukopenia (2% vs 1%), vomiting (1% vs 2%), and abdominal pain (1% vs 2%).
Fifty-four percent of patients who received olaparib plus bevacizumab required dose interruptions versus 24% of those who received bevacizumab alone; 41% versus 7%, respectively required dose reductions. Lastly, 20% of patients on the investigational arm discontinued treatment versus 6% of those on the control arm.
Updated data from the trial were presented during the 2020 ESMO Virtual Congress pertaining to response rates for patients with evidence of disease per RECIST criteria and/or CA-125 criteria at study entry. Results showed that the overall response rates (ORRs) per RECIST criteria were 30% and 25% with the combination and the monotherapy, respectively, in the overall population.4
When broken down by subgroup, the combination elicited an ORR of 64% in patients with BRCA mutations (n = 47) versus 42% with bevacizumab alone. The ORRs with the combination and the monotherapy were 53% versus 31%, respectively, in those with HRD positivity including BRCA mutations (n = 81), 32% versus 21% for those with HRD positivity without BRCA mutations (n = 33), and 13% versus 15% in those with HRD negativity (n = 83).
Additionally, the CA-125 response rates in the overall population with the olaparib combination and bevacizumab alone were 36% versus 29%, respectively. When broken down by subgroup, the CA-125 response rates with the combination in patients with BRCA-positive disease was 83% with olaparib/bevacizumab versus 60% with bevacizumab alone; 70% versus 63%, respectively, in those with HRD positivity, 50% versus 67%, respectively, in those with HRD positivity and BRCA negativity, and 20% versus 0%, respectively, in those with HRD negativity.
“Half of all newly diagnosed patients with advanced ovarian cancer have HRD-positive tumors,” Dave Fredrickson, executive vice president of the Oncology Business Unit, at AstraZeneca, added in the release. “Women treated with [olaparib] in combination with bevacizumab in the PAOLA-1 phase 3 trial lived progression free for a median of more than 3 years, showing that HRD testing should be an essential component of clinical diagnosis. HRD status can help physicians select a personalized first-line treatment regimen for patients to substantially delay relapse in this devastating disease.”
In May 2020, the FDA approved olaparib in combination with bevacizumab as maintenance treatment for patients with advanced ovarian cancer who are in complete or partial response to frontline platinum-based chemotherapy based on data from PAOLA-1.
Previously, in December 2018, the FDA approved olaparib for use as a maintenance therapy in 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 based on data from the phase 3 SOLO-1 trial.