Following potential safety concerns with 3 PARP inhibitors, manufactures have voluntarily elected to withdraw the indications for patients with heavily pretreated patients with BRCA-mutated ovarian cancer.
Emerging safety concerns have prompted manufacturers to voluntarily withdraw indications for the 3 PARP inhibitors for patients with heavily pretreated BRCA-mutated ovarian cancer: niraparib (Zejula), olaparib (Lynparza), and rucaparib (Rubraca). The indication withdrawals do not affect all patient populations and prescribers are encouraged to refer to the latest labels and discuss treatment courses with their patients receiving these medications.
Niraparib was indicated for use with patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with 3 or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD)–positive status.
The company notified providers September 14, 2022, that investigators identified “a potential detrimental effect” on overall survival (OS) in patients treated other PARP inhibitors in trials evaluating niraparib as third-line or later therapy for patients with a BRCA-mutated advanced ovarian cancer.1
The FDA approved niraparib for patients with HRD-positive advanced ovarian cancer in October 2019 based on data from the single-arm QUADRA Study (NCT02354586) evaluating the agent vs placebo.1 The overall response rate (ORR) was 24% (95% CI, 16%-34%) in patients with HRD positivity, consisting of all partial responses. The estimated median DOR was 8.3 months (95% CI, 6.5–not estimable).
In patients with tumor BRCA mutations and platinum-sensitive disease, the ORR was 39% (95% CI, 17%-64%) compared with 29% (95% CI, 11%-52%) in patients with platinum-resistant disease and 19% (95% CI, 4%-46%) in patients with platinum-refractory disease.1
This does not affect niraparib’s other approved uses: for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy or for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
The FDA's Oncologic Drugs Advisory Committee is scheduled to review data on niraparib as a maintenance treatment for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers who are in complete or partial response to platinum-based chemotherapy during its November meeting.
GSK’s move comes on the heels of an August decision by AstraZeneca and Merck. The companies voluntarily withdrew accelerated approval for olaparib for adults with BRCA-mutated advanced ovarian cancer who have received at least 3 prior lines of chemotherapy.
On August 26, 2022, AstraZeneca and Merck notified providers that olaparib was no longer indicated for this population following a safety analysis of the phase 3 SOLO3 trial (NCT02282020).4 Olaparib induced similar overall survival (OS) results as nonplatinum chemotherapy in heavily pretreated patients with BRCA-mutated, platinum-sensitive relapsed ovarian cancer with BRCA mutations in SOLO3.
At a median follow-up of 48.9 months in patients who received 2 or more lines of prior chemotherapy, olaparib monotherapy elicited a median OS of 34.9 months. At a median follow-up of 25.4 months, patients who were administered chemotherapy experienced a median OS of 32.9 months (HR, 1.07; 95% CI, 0.76-1.49).
However, a subgroup analysis found “a potential survival detriment.” In an evaluation of patients who received at least 2 lines of therapy, 65.2% of those who received olaparib died by the April 2021 data cut-off compared with 52.3% of those assigned to chemotherapy. For patients who received 3 or more prior lines of chemotherapy, 70.0% of patients in the olaparib arm had died compared with 54.8% of those assigned to chemotherapy.4
In June 2022, Clovis pulled the indication of rucaparib for BRCA-mutated ovarian cancer after at least 3 prior chemotherapies in the United States and Europe. The FDA granted accelerated approval to the PARP inhibitor in December 2016 for the treatment of patients with deleterious BRCA mutation (germline and/or somatic)–associated advanced ovarian cancer following 2 or more chemotherapies. In 2 open-label, single-arm trials, investigator-assessed ORR was 54% with a median duration of response of 9.2 months.5
The company included preliminary OS data from the ARIEL3 trial (NCT01968213) in a filing with the US Securities and Exchange Commission made June 16, 2022.6 In the tBRCA population, HR was 0.832 (nominal P-value = .3162). HR was 1.005 (nominal P-value = .9693) in the HRD population. The HR was 0.995 (nominal P-value = .9621) in the intent-to-treat population.
Clovis said it plans to present full OS data from the ARIEL3 trial, including for the exploratory subgroups, at the 2022 Annual Global Meeting of the International Gynecological Cancer Society beginning September 29.
The European Medicines Agency in July recommended restricting the use of rucaparib. The agency noted the agent induced an OS of 19.4 months vs 25.4 months with chemotherapy.7