FDA approves talazoparib with enzalutamide for HRR-mutated mCRPC

July 2023 Cancer trials Robin van Amersfoort
Conceptual image for viral ethiology of prostate cancer. 3D illustration showing Human Papilloma Viruses HPV infecting prostate gland which develops cancerous tumor

In a significant breakthrough for treating metastatic castration-resistant prostate cancer (mCRPC), the U.S. Food and Drug Administration (FDA) has approved the combination therapy of talazoparib with enzalutamide for patients with homologous recombination repair (HRR) gene-mutated mCRPC on the 20th of June 2023.

The FDA approval was based on the results of the randomised, double-blind, placebo-controlled, multi-cohort trial TALAPRO-2, enrolling 399 patients with HRR gene-mutated mCRPC.1 Patients were randomised (1:1) to receive enzalutamide 160 mg daily plus either talazoparib 0.5 mg or placebo daily. Patients were required to have a prior orchiectomy and, if not performed, received gonadotropin-releasing hormone (GnRH) analogues. Patients with prior systemic therapy for mCRPC were excluded. However, prior CYP17 inhibitors or docetaxel for metastatic castration-sensitive prostate cancer (mCSPC) were permitted. Randomisation was stratified by previous treatment with a CYP17 inhibitor or docetaxel. HRR genes (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) were assessed prospectively using tumour tissue and/or circulating tumour DNA (ctDNA)-based next generation sequencing assays.

The major efficacy outcome measure was radiographic progression-free survival (rPFS) per RECIST version 1.1 for soft tissue and Prostate Cancer Working Group 3 criteria for bone, assessed by blinded independent central review.


A statistically significant improvement in rPFS for talazoparib with enzalutamide compared to placebo with enzalutamide was observed in the HRR gene-mutated population, with a median that was not reached vs 13.8 months (hazard ratio (HR) 0.45; 95% CI: 0.33, 0.61; p<0.0001). In an exploratory analysis by BRCA mutation status, the HR for rPFS in patients with BRCA-mutated mCRPC (n=155) was 0.20 (95% CI: 0.11-0.36) and, in patients with non-BRCAm HRR gene-mutated mCRPC, HR was 0.72 (95% CI: 0.49-1.07).


The most common adverse reactions (≥10%), including laboratory abnormalities, were decreased levels of haemoglobin, neutrophils, lymphocytes and platelets, as well as decreased levels of calcium, sodium, potassium, magnesium and phosphate, reduced appetite, fatigue, nausea, fractures, dizziness, increased bilirubin, and dysgeusia. Among all patients with mCRPC treated with talazoparib with enzalutamide in the TALAPRO-2 study, 39% required a blood transfusion, including 22% who required multiple transfusions, and 2 patients were diagnosed with myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML).


The FDA’s approval of the combination therapy of talazoparib with enzalutamide is a significant milestone in the management of mCRPC with HRR gene mutations. The TALAPRO-2 trial demonstrated substantially improved rPFS and objective response rates in the combination therapy group compared to enzalutamide monotherapy. These findings highlight the importance of targeting HRR gene mutations to enhance the efficacy of current therapies and extend survival for patients with mCRPC.


  1. Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial [published online ahead of print, 2023 Jun 2]. Lancet. 2023;S0140-6736(23)01055-3.