FDA Approves Talazoparib Plus Enzalutamide for mCRPC With HRR Gene Mutations

The FDA granted approval to the oral poly ADP-ribose polymerase (PARP) inhibitor talazoparib (Talzenna; Pfizer) in combination with standard-of-care enzalutamide (Xtandi) for patients with metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene mutations.¹

The approval was based on data from the phase 3 TALAPRO-2 trial (NCT03395197), in which patients treated with talazoparib plus enzalutamide showed statistically significant improvement in radiographic progression-free survival (rPFS), the primary end point, vs patients who received a placebo plus enzalutamide. The FDA previously granted priority review to the supplemental new drug application for the combination treatment.

“Despite treatment advancement in metastatic castration-resistant prostate cancer, the disease can progress quickly, and many patients may only receive one line of therapy. Therefore, new first-line treatment options are needed to reduce the risk of disease progression or death. For patients with mCRPC harboring HRR genetic alterations, outcomes are even worse,” said lead TALAPRO-2 investigator Neeraj Agarwal, MD, FASCO, in a news release.² HRR mutations are present in about a quarter of mCRPC cases.

The 2-part, randomized, double-blind, placebo-controlled TALAPRO-2 study included 2 cohorts: all-comers (n = 805) and patients with HRR mutations (n = 399). RECIST version 1.1 for soft tissue and Prostate Cancer Working Group 3 criteria for bone were used to determine rPFS via blinded independent central review. HRR mutations were identified by tumor tissue and/or circulating tumor DNA–based next generation sequencing assays.

In the HRR gene mutation cohort, patients treated with talazoparib showed a statistically significant and clinically meaningful improvement in rPFS. The median rPFS was not reached in the talazoparib cohort and was 13.8 months in patients receiving placebo, with talazoparib plus enzalutamide demonstrating a 55% lower risk of disease progression or death compared with the placebo plus enzalutamide (HR, 0.45; 95% CI, 0.33-0.61; P < .0001).

An exploratory analysis of rPFS stratified by BRCA mutation status showed HRs of 0.20 (95% CI, 0.11-0.36) in patients with BRCA mutations and 0.72 (0.49-1.07) in patients with non–BRCA-mutated, HRR gene–mutated mCRPC.

Patients who underwent previous systemic therapy for mCRPC were excluded from the trial, but patients treated with CYP17 inhibitors or docetaxel for metastatic castration-sensitive prostate cancer were included. Prior orchiectomy was a requirement, but if orchiectomy had not been performed, those patients received gonadotropin-releasing hormone analogs.

Common adverse reactions, all occurring in less than 10% of the population, included decreased hemoglobin, decreased neutrophils, decreased lymphocytes, fatigue, decreased platelets, decreased calcium, nausea, decreased appetite, decreased sodium, decreased phosphate, fractures, decreased magnesium, dizziness, increased bilirubin, decreased potassium, and dysgeusia.

In the United States, talazoparib is indicated for the treatment of deleterious or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer. A marketing authorization application for combination talazoparib with enzalutamide has been accepted by the European Medicines Agency for review.²

References

1. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA. June 20, 2023. Accessed June 21, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate
2. Pfizer’s Talzenna in combination with Xtandi receives U.S. FDA approval. News release. Pfizer. June 20, 2023. Accessed June 21, 2023. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-talzennar-combination-xtandir-receives-us-fda