The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion for olaparib as maintenance treatment in adult patients with advanced, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response after first-line platinum-based chemotherapy plus bevacizumab and whose disease has homologous recombination deficiency positivity defined by either a BRCA1/2 mutation and/or genomic instability.
José Baselga, MD, PhD
The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for olaparib (Lynparza) as maintenance treatment in adult patients with advanced, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response after first-line platinum-based chemotherapy plus bevacizumab (Avastin) and whose disease has homologous recombination deficiency (HRD) positivity defined by either a BRCA1/2 mutation and/or genomic instability.1
The recommendation for approval was based on data from a biomarker subgroup analysis of the phase 3 PAOLA-1 trial (NCT02477644), which had been published in the New England Journal of Medicine.2 Results from the trial showed that the addition of olaparib to bevacizumab maintenance treatment resulted in a 67% reduction in the risk of disease progression or death (HR, 0.33; 95% CI, 0.25-0.45) in patients with HRD-positive tumors, including those that harbored a BRCA mutation.3
In this subgroup, the median progression-free survival (PFS) with olaparib/bevacizumab was 37.2 months versus 17.7 months with bevacizumab alone. For those with HRD positivity who did not harbor a BRCA mutation, the median PFS with the olaparib combination was 28.1 months versus 16.6 months with bevacizumab alone (HR, 0.43; 95% CI, 0.28-0.66).
“Half of all patients with advanced ovarian cancer have HRD-positive tumors. [Olaparib] together with bevacizumab has demonstrated a median PFS benefit of more than 3 years versus 17.7 months with bevacizumab alone, offering new hope for women in this setting,” José Baselga, MD, PhD, stated in a press release. “This recommendation is a vital step toward addressing a large and critical unmet need and could bring a new treatment option that significantly delays relapse in this difficult-to-treat disease.”
The double-blind, placebo-controlled, phase 3 PAOLA-1 trial enrolled patients with newly diagnosed, advanced, FIGO stage III to IV, high-grade, serous or endometrioid ovarian, fallopian tube, or peritoneal cancer who had achieved a complete response (CR) or partial response (PR) to frontline platinum-based chemotherapy and bevacizumab, irrespective of genetic biomarker status or outcome before surgery.
Participants were randomized in a 2:1 fashion to received either olaparib/bevacizumab (n = 537) or bevacizumab/placebo (n = 269) for frontline maintenance treatment. Bevacizumab was given at a dose of 15 mg/kg every 3 weeks on day 1 of the treatment cycle. In the experimental arm, olaparib was administered at a dose of 300 mg twice daily.
The primary end point of the trial was investigator-assessed PFS, while key 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.
With regard to safety, the most common toxicities reported in 20% or more patients in the investigational and control arms, respectively, included fatigue (53% vs 32%), 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%).
Updated results from the trial were presented during the 2020 ESMO Virtual Congress on response rates for patients with evidence of disease per RECIST criteria and/or CA-125 criteria at study entry. Here, the ORRs per RECIST criteria were 30% with olaparib/bevacizumab versus 25% with bevacizumab alone in the overall population.4
When broken down by subgroup, those with BRCA mutations (n = 47) experienced ORRs of 64% with the combination versus 42% with bevacizumab alone; 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).
Moreover, the CA-125 response rate in the overall population with olaparib/bevacizumab was 36% versus 29% with bevacizumab alone. When broken down by subgroup, the CA-125 response rates with the combination in BRCA-positive patients was 83% versus 60% with bevacizumab alone; 70% versus 63%, respectively in those with HRD positivity, 50% versus 67% in those with HRD positivity and BRCA negativity, and 20% versus 0% in those with HRD negativity.
In May 2020, the FDA approved olaparib in combination with bevacizumab for the maintenance treatment of patients with advanced ovarian cancer who are in complete or partial response to frontline platinum-based chemotherapy based on findings from PAOLA-1.
Previously, in December 2018, the FDA approved olaparib for use as a maintenance treatment 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.