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Lynparza FDA Approved, in Combination With Abiraterone and Prednisone (or Prednisolone), for Metastatic Castration-Resistant Prostate Cancer With BRCA Mutation

June 2023 Vol 16, No 1 - FDA Approvals

On May 31, 2023, the FDA approved a new indication for olaparib (Lynparza; AstraZeneca Pharmaceuticals), a poly (ADP-ribose) polymerase inhibitor, in combination with abiraterone and prednisone (or prednisolone), for adults with deleterious or suspected deleterious BRCA mutation–positive, metastatic, castration-resistant prostate cancer (CRPC), as determined by an FDA-approved test.

Olaparib was previously approved as monotherapy for patients with metastatic CRPC and deleterious or suspected deleterious germline or somatic homologous recombination repair gene mutation–positive, metastatic CRPC whose disease progressed after previous treatment. The drug also has received various approvals for the treatment of ovarian, breast, and pancreatic cancers.

The current FDA approval was based on results from the phase 3 PROpel clinical trial (NCT03732820) of 796 patients with metastatic CRPC. Patients were randomized 1:1 to olaparib with abiraterone or to placebo with abiraterone, and received prednisone or prednisolone. To be included in the trial, patients had to have a previous orchiectomy or, if not, had to have received gonadotropin-releasing hormone (GnRH) analogs. Patients were excluded if they had received systemic therapy for metastatic CRPC, but previous treatment with docetaxel for metastatic hormone-sensitive prostate cancer was allowed. Randomization was stratified by previous docetaxel treatment and site of metastases. Retrospective testing for BRCA mutational status, with the FoundationOne CDx and FoundationOne Liquid CDx tests, was performed on all available clinical samples.

The major efficacy measure was investigator-assessed radiologic progression-free survival (PFS), with overall survival (OS) as an additional end point.

Patients who received olaparib plus abiraterone had a significant improvement in radiologic PFS compared with patients who received placebo plus abiraterone in the intent-to-treat (ITT) population. In the 85 patients with a BRCA mutation (11% of the ITT population), an exploratory subgroup analysis revealed a median radiologic PFS that was not reached with olaparib plus abiraterone compared with 8 months (95% confidence interval [CI], 6-15) with placebo plus abiraterone (hazard ratio [HR], 0.24; 95% CI, 0.12-0.45). In this subgroup, the OS HR was 0.3 (95% CI, 0.15-0.59). The subgroup of patients without a BRCA mutation (n=711; 89% of ITT population) had a radiologic PFS HR of 0.77 (95% CI, 0.63-0.96) and an OS HR of 0.92 (95% CI, 0.74-1.14), suggesting that the radiologic PFS improvement in the ITT population was mainly attributable to patients with the BRCA mutation.

The most common (≥10%) adverse events with olaparib plus abiraterone were anemia (48%), fatigue (38%), nausea (30%), diarrhea (19%), decreased appetite (16%), lymphopenia (14%), dizziness (14%), and abdominal pain (13%). A total of 72 (18%) patients needed ≥1 blood transfusions and 46 (12%) needed multiple transfusions.

“Preventing or delaying radiographic progression or death is an important clinical end point in assessing cancer treatment and is very important to patients, their caregivers, and their families,” said Andrew Armstrong, MD, MSc, of Duke Cancer Institute, Durham, NC, and a trial investigator. “The PROpel results showed the Lynparza combination demonstrated a notable clinically meaningful benefit that should rapidly be considered as the standard-of-care treatment for patients with BRCA-mutated metastatic castration-resistant prostate cancer.”

A twice-daily 300-mg dose of olaparib is recommended, taken orally with or without food. For abiraterone, the recommended dose is 1000 mg orally once daily. Abiraterone should be given twice daily with 5 mg of oral prednisone or prednisolone. In addition, patients should receive a GnRH analog concurrently or should have had a bilateral orchiectomy.

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Last modified: June 2, 2023