Final survival data from the TALAPRO-2 study support the use of a PARP inhibitor plus an androgen receptor pathway inhibitor
Co-inhibition for the treatment of metastatic castration-resistant prostate cancer (mCRPC) have emerged as a promising therapeutical strategy in recent years with the use of PARP inhibitors, which suppress androgen receptor transcriptional activity, and androgen receptor inhibitors (ARPI), which demonstrated to upregulate PARP activity and downregulate homologous recombination repair (HRR) gene expression. Meaningful overall survival improvement for the combination of the PARP inhibitor talazoparib (TALA) plus the ARPI Enzalutamide (ENZA) versus placebo plus ENZA as first-line systemic treatment for patients with or without prior abiraterone or docetaxel treatment for metastatic hormone-sensitive disease (mHSPC) was reported in the randomised phase III TALAPRO-2 trial.
In the study, two cohorts were recruited subsequently: Cohort 1 with all comers unselected for homologous recombination repair (HRR) gene mutations (N = 805 patients of which N = 169 harboured a HRR gene mutation) and Cohort 2 with an additional 230 patients with known HRR gene mutations. The study reported a substantial radiographic progression-free survival (rPFS) improval – the primary endopoint – with the combination therapy in Cohort 1 (Lancet. 2023 Jul 22;402(10398):291-303), and this led to approval of the combination of TALA/ENZA for men with mCRPC in whom chemotherapy was not indicated by the European Medicines Agency (EMA) in November 2023. Due to a more profound rPFS improval in HRR gene mutation harbouring patients, the U.S. Food and Drug Administration (FDA) has so far only approved the TALA/ENZA combination for mCRPC patients with a genomic HRR defect in June 2023.
At the 2025 ASCO Genitourinary Cancers Symposium, the final survival endpoint analysis of the TALAPRO-2 was presented for both the all comer cohort and for patients with HRR-deficiency (J Clin Oncol 2025; 43(5_suppl); LBA18). After a median follow-up of 53 months, the beneficial impact of TALA/ENZA on rPFS (primary endpoint) was confirmed (33.1 versus 19.1 months, hazard ratio (HR) 0.667; 95% confidence interval, 0.551-0.807). Importantly, in the TALAPRO-2 trial the rPFS benefit also translates into an overall benefit in unselected mCRPC patients. The median overall survival (OS) in Cohort 1 was 45.8 months with TALA/ENZA compared to 37.0 months in patients treated with Placebo + ENZA (median OS improvement of 8.8 months), which translated into a risk reduction of death by 20% (HR 0.796; 95%-CI, 0.661-0.958). A trend towards an OS benefit was also noted for patients without a BRCA alteration or any HRR defect in subgroup analyses. Among all subgroups (all comers, HRR non-deficient and HRR-deficient), a similar median OS of 45-47 months was achieved with TALA/ENZA combination treatment, which has so far not been reached in this patient population.
Moreover, no new safety signals were identified. Still, the addition of TALA is associated with a clear increase in ≥ grade 3 treatment-emergent adverse events (75.9 versus 44.6%). 54.4% of patients required a dose reduction of TALA and 21.6% discontinued TALA due to adverse events. Anaemia was the most prominent emerging side effect from adding TALA to ENZA, with 49% of patients suffering grade 3-4 anaemia with a median time to onset of this of 3.3 months. 42.2% of patients required red blood cell transfusions and 8.5% of patients discontinued TALA due to anaemia.
The combination of TALA/ENZA is therefore confirmed as a valuable first-line treatment option in mCRPC without a need for HRR gene mutation testing. Still, HRR gene mutation testing will help identify patients who derive the most prominent risk reduction of death. Interestingly, the PROpel trial testing the combination of abiraterone plus olaparib in the same setting had failed to achieve a significant OS improvement over abiraterone plus placebo in the prespecified final OS analysis (Lancet Oncol. 2023 Oct;24(10):1094-1108). Of note, it remains unclear whether patients treated with an ARPI other than abiraterone as first-line treatment for metastatic hormone-sensitive prostate cancer (mHSPC) may derive a similar benefit, as these patients were not recruited in the TALAPRO-2 trial, but ARPIs, such as ENZA, apalutamide or arolutamide are now frequently used in this setting.
