Combining PARP inhibition and androgen receptor-signalling inhibition improves radiographic progression-free survival in HRR-deficient mCRPC

Adding the PARP inhibitor talazoparib to enzalutamide significantly improved radiographic progression-free survival (rPFS) and time to deterioration of quality-of-life in men with metastatic castration-resistant prostate cancer (mCRPC) harbouring homologous recombination repair (HRR) gene alterations in the phase 3 TALAPRO-2 study.

For patients with mCRPC, a current standard-of-care treatment is androgen receptor-signalling inhibition with enzalutamide. In addition, PARP inhibitor talazoparib monotherapy showed durable anti-tumour activity in heavily pre-treated patients with mCRPC harbouring HRR gene alterations (HRR-deficient) [1]. The aim of the phase 3 TALAPRO-2 trial (NCT03395197) was to evaluate the efficacy and safety of first-line talazoparib plus enzalutamide in men with mCRPC. Recently, the Cohort 1 (i.e. both non-HRR-deficient and HRR-deficient participants) results were presented [2]. Currently, Prof. Karim Fizazi (Institute Gustave Roussy, France) presented results from Cohort 2 (i.e. HRR-deficient population) [3].

In Cohort 2, 399 participants were randomised 1:1 to talazoparib/enzalutamide or placebo/enzalutamide. Tumour samples were assessed for HRR gene alteration (i.e. BRCA1, BRCA2, PALB2, ATM, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12). The most common alterations were BRCA2, ATM, CDK12, and CHEK2. The primary endpoint of TALAPRO-2 was rPFS.

The addition of talazoparib to enzalutamide significantly improved rPFS. After a median follow-up of 17 months, median rPFS was not reached in the talazoparib/enzalutamide arm compared with 13.8 months in the placebo/enzalutamide arm (HR 0.45; P<0.0001), leading to a 55% reduced risk of progression or death (see Figure). Benefit of talazoparib/enzalutamide was observed in all prespecified subpopulations. Of note, benefit was most prominent in patients with BRCA1/2 gene alterations (HR 0.20; P<0.0001). Overall survival outcomes are showing a trend toward a benefit of talazoparib but are not yet mature (HR 0.69; P=0.68).

Figure: Primary endpoint (rPFS) in the HRR-deficient Cohort 2 of the TALAPRO-2 study [1]



CI, confidence interval; ENZA, enzalutamide; HR, hazard ratio; HRR, harbouring homologous recombination repair; PBO, placebo; rPFS, radiographic progression-free survival; TALA, talazoparib.

In addition, talazoparib favoured objective response rate (67.1 vs 40.0%; P=0.0015), time to PSA progression (median 28.6 vs 11.1 months; HR 0.41; P<0.0001), time to cytotoxic chemotherapy (median not yet reached; HR 0.46; P=0.0001), and time to clinically meaningful deterioration of quality-of-life (median 27.1 vs 19.3 months; HR 0.69; P=0.032).

The addition of talazoparib to enzalutamide increased treatment-related adverse effects (TRAEs) grade 3–4 (66.2 vs 37.2%). The most common TRAEs leading to dose reduction of talazoparib were anaemia (42.9%), neutropaenia (15.2%), and thrombocytopaenia (5.6%).

“Talazoparib in combination with enzalutamide, if approved, has the potential to become a first-line treatment option for patients with mCRPC and HRR gene alterations,” concluded Prof. Fizazi.

1. De Bono JS, et al. Lancet Oncol. 2021;22:1250–1264.
2. Agarwal N, et al. The Lancet 2023;June 4. DOI:10.1016/S0140-6736(23)01055-3.
3. Fizazi K, et al. TALAPRO-2: phase 3 study of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line treatment for patients with metastatic castration-resistant prostate cancer harboring homologous recombination repair gene alterations (HRR-deficient population). Abstract 5004, ASCO Annual Meeting 2023, 2–6 June, Chicago, USA.

 

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Posted on 2 August, 20232 August, 2023