The combination of the PARP inhibitor talazoparib plus the androgen receptor-pathway inhibitor enzalutamide yields a clinically meaningful increase in the overall survival (OS) of patients with metastatic castration-resistant prostate cancer (mCRPC) being treated in the first-line setting when compared with enzalutamide alone, according to final data from the phase III TALAPRO-2 trial.

Over a median follow-up of 52.5 months, there was a 20-percent reduction in the risk of death, with an 8.8-month improvement in median OS in the talazoparib plus enzalutamide arm vs the enzalutamide arm (45.8 vs 37.0 months; hazard ratio [HR], 0.796, 95 percent confidence interval [CI], 0.661?0.958; p=0.0155), reported Dr Neeraj Agarwal from the Huntsman Cancer Institute at the University of Utah in Salt Lake City, Utah, US. [ASCO GU 2025, abstract LBA18]

Notably, the OS gain with talazoparib plus enzalutamide was especially pronounced in subgroups of patients with HRR gene alterations (HR, 0.622, 95 percent CI, 0.475?0.814; p=0.0005) and those with BRCA1/2 alterations (HR, 0.497, 95 percent CI, 0.318?0.776; p=0.0017), as shown in data presented by Dr Karim Fizazi from the Gustave Roussy Institute of Oncology in Villejuif, France. [ASCO GU 2025, abstract LBA141]

But even in those with no detectable HRR deficiency (HR, 0.782, 95 percent CI, 0.582?1.050; p=0.1008) or BRCA alteration (HR, 0.749, 95 percent CI, 0.582?0.963; p=0.0237), OS also favoured the combination, Agarwal added.

Updated PFS and safety data

With around 2 years of additional follow-up, statistically significant and clinically meaningful benefit in the primary endpoint of radiographic progression free survival (rPFS) was maintained in the talazoparib plus enzalutamide arm, according to Agarwal. The median rPFS was 33.1 months with the combination therapy vs 19.5 with enzalutamide alone?a 13.6-month difference (HR, 0.667, 95 percent CI, 0.551?0.807; p<0.0001).

The same was true for the subgroup of patients with HRR gene alterations, with the median rPFS being 30.7 months in the combination arm vs 12.3 months in the enzalutamide arm (HR, 0.468, 95 percent CI, 0.359?0.612; p<0.0001), Fizazi reported.

No new safety risks were identified during the extended 2-year monitoring period. The most common grade 3/4 treatment-emergent adverse events observed with talazoparib plus enzalutamide vs enzalutamide monotherapy were anaemia (49.0 percent vs 4.5 percent) and neutropenia (19.3 percent vs 1.5 percent).

No additional cases of myelodysplastic syndromes or acute myeloid leukaemia were observed beyond the one case of each that had been previously reported, Agarwal said. [Lancet 2023;402:291-303]

Toxicity led to talazoparib dose interruption in 65.3 percent, dose reduction in 54.5 percent, and discontinuation in 21.6 percent of patients.

Standard of care

Overall, the TALAPRO-2 data support talazoparib plus enzalutamide as a standard of care for the treatment of mCRPC, said ASCO discussant Dr William Kevin Kelly from the Thomas Jefferson University Hospital in Philadelphia, US.

However, Kelly stressed the importance of a thorough risk-benefit assessment of the combination, especially in patients with HRR gene alterations or with unknown HRR status.

Additionally, more research is needed to define the optimal placement of talazoparib-enzalutamide within the current treatment landscape for advanced prostate cancer, he said.

TALAPRO-2 population

TALAPRO-2 comprised two patient cohorts: an unselected cohort of 805 patients (including 169 with HRR gene alterations) and a subsequent cohort of 399 patients with HRR gene alterations (230 additional patients enrolled). All patients had untreated mCRPC and an Eastern Cooperative Oncology Group status of 0 or 1 at baseline and were on ongoing androgen deprivation therapy.

The patients were randomized to receive enzalutamide in combination with either talazoparib (n=402) or placebo (n=403). At baseline, the median age of the unselected patient cohort was 71 years, and 61.9 percent were White. The median PSA was 18.2 ng/mL in the talazoparib plus enzalutamide arm and 16.2 ng/mL in the enzalutamide arm. The median duration of treatment with talazoparib was 19.7 months.

By the final data cutoff, quality of life, assessed using the Patient-reported Global Health Status/QoL per EORTC QLQ-C30, had been maintained in the talazoparib plus enzalutamide arm. The median time to definitive deterioration was 41.5 months in the combination arm vs 34.1 months in the enzalutamide arm (HR, 0.878, 95 percent CI, 0.704?1.096; p=0.2487).