On May 8, 2020, the U.S. Food and Drug Administration (FDA) expanded the indication of olaparib (Lynparza®) to include its combination with bevacizumab for first-line maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response 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 or genomic instability.
FDA also approved the Myriad myChoice® CDx as a companion diagnostic for olaparib.
Efficacy of the new indication was investigated in a randomized, double-blind, placebo-controlled, multicenter trial (PAOLA-1; NCT03737643) comparing olaparib with bevacizumab versus placebo plus bevacizumab in patients with advanced, high-grade epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer following first-line platinum-based chemotherapy and bevacizumab.
Randomization was stratified by first-line treatment outcome and tumor BRCA mutation status determined by prospective local testing. All available clinical samples were retrospectively tested with Myriad myChoice® CDx.
Patients were randomized 2:1 to receive 300 mg of olaparib orally twice daily in combination with bevacizumab (n = 537) 15 mg/kg every three weeks or placebo plus bevacizumab (n = 269). Patients continued bevacizumab in the maintenance setting and started olaparib after a minimum of three weeks and up to a maximum of nine weeks following their last chemotherapy dose. Olaparib was continued for up to two years or until disease progression or unacceptable toxicity occurred.
The major efficacy outcome measure was investigator-assessed progression-free survival (PFS), evaluated according to response evaluation criteria in solid tumors 1.1. An additional efficacy endpoint was overall survival (OS). Estimated median PFS in the subgroup of 387 patients with HRD-positive tumors was 37.2 months in the olaparib with bevacizumab arm and 17.7 months in the placebo plus bevacizumab arm (HR 0.33; 95% CI = 0.25-0.45). Results from a blinded independent review of PFS were consistent with the investigator assessed PFS analysis. OS data were not mature.
The most common adverse reactions (≥ 10%) were nausea, fatigue (including asthenia), anemia, lymphopenia, vomiting, diarrhea, neutropenia, leukopenia, urinary tract infection, and headache.
The recommended olaparib dose is 300 mg taken orally twice daily, with or without food. When used with olaparib, the recommended bevacizumab dose is 15 mg/kg by IV every three weeks.
The review used the Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment.
FDA granted the application priority review and orphan product designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.
For assistance with single-patient oncology investigational new drug applications, contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.