Highlights
– TALAPRO-2 final analyses show a statistically significant overall survival (OS) benefit when talazoparib is added to enzalutamide in men with metastatic castration‑resistant prostate cancer (mCRPC), both in HRR‑deficient and unselected populations.
– The survival advantage is most pronounced in patients with BRCA1/2 alterations (HR ~0.50 in HRR‑deficient cohort; HR 0.55 in unselected HRR‑deficient subgroup), with a doubling of 4‑year OS in the BRCA subgroup.
– Combination therapy substantially prolongs radiographic progression‑free survival (rPFS) but is associated with expected hematologic toxicity (notably high rates of grade ≥3 anemia and neutropenia).
Background: clinical need and biological rationale
Metastatic castration‑resistant prostate cancer (mCRPC) remains a lethal disease despite multiple active agents (ARPIs, taxanes, radioligands). A subset of mCRPC tumors harbour deleterious alterations in homologous recombination repair (HRR) genes — most notably BRCA1 and BRCA2 — that confer sensitivity to poly(ADP‑ribose) polymerase (PARP) inhibitors through synthetic lethality. Preceding randomized data supported PARP inhibitor activity in HRR‑altered mCRPC, and preclinical/early clinical data suggested potential synergy combining PARP inhibition with androgen receptor pathway inhibitors (ARPIs) such as enzalutamide. TALAPRO‑2 tested talazoparib (a potent PARP inhibitor) plus enzalutamide as initial therapy for mCRPC, evaluating outcomes both in an HRR‑deficient cohort and an unselected population.
Study designs and patient populations
Two related randomized, double‑blind, placebo‑controlled phase 3 reports from the TALAPRO‑2 program were published in Lancet (2025): one reporting the HRR‑deficient cohort (Fizazi et al.) and the other the genetically unselected cohort (Agarwal et al.). Key common features:
- Population: adult men with asymptomatic or mildly symptomatic mCRPC on continued androgen deprivation therapy and no prior life‑prolonging therapy for castration‑resistant disease.
- Intervention: talazoparib 0.5 mg once daily plus enzalutamide 160 mg once daily versus enzalutamide plus placebo; enzalutamide was open label, talazoparib/placebo double blinded.
- Primary endpoint: rPFS by blinded independent central review. Overall survival (OS) was a key, alpha‑protected secondary endpoint with predefined significance thresholds for final analysis.
- Follow‑up for final OS analysis: median ~44.2 months in the HRR‑deficient cohort and ~52.5 months in the unselected cohort.
Key results: efficacy
Both reports demonstrate clinically meaningful benefit when talazoparib is combined with enzalutamide. Main efficacy results are summarized in the table below for direct comparison.
| Population | Patients (n) | Median rPFS (tal+enz vs enz) | rPFS HR (95% CI) | Median OS (tal+enz vs enz) | OS HR (95% CI) | Notable subgroup |
|---|---|---|---|---|---|---|
| HRR‑deficient cohort (Fizazi et al.) | 399 (200 vs 199) | 30.7 vs 12.3 months | 0.47 (0.36–0.61), p<0.0001 | 45.1 mo (95% CI 35.4–NR) vs 31.1 mo (27.3–35.4) | 0.62 (0.48–0.81), p=0.0005 (significant) | BRCA1/2 (n=155): OS HR 0.50 (0.32–0.78) |
| Genetically unselected cohort (Agarwal et al.) | 805 (402 vs 403) | 33.1 vs 19.5 months | 0.67 (0.55–0.81), p<0.0001 | 45.8 mo (39.4–50.8) vs 37.0 mo (34.1–40.4) | 0.80 (0.66–0.96), p=0.016 (significant) | HRR‑deficient subgroup (n=169): OS HR 0.55 (0.36–0.83) |
Interpretation of these data points:
- In the prospectively selected HRR‑deficient population, talazoparib plus enzalutamide produced a large rPFS benefit (median 30.7 vs 12.3 months) and a robust OS improvement (HR 0.62), surpassing the trial’s pre‑specified alpha boundary.
- The survival benefit was greatest in patients with BRCA1/2 alterations (HR ~0.50), with a striking difference in 4‑year OS rates reported (53% vs 23% in the HRR‑deficient analysis).
- In the genetically unselected cohort, an overall OS benefit was also observed (HR 0.80), but effect size was attenuated compared with the HRR‑selected cohort and the benefit concentrated in HRR‑deficient patients within that trial.
Safety and tolerability
The safety profile was consistent with known toxicities of talazoparib and the combination. Hematologic adverse events predominated:
- HRR‑deficient cohort: grade ≥3 anemia in 43% and neutropenia in 20% of patients receiving talazoparib plus enzalutamide.
- Unselected cohort: similar findings with grade ≥3 anemia in ~49% and neutropenia in ~19% in the talazoparib arm (versus 4% and 1% respectively in placebo arm).
Other adverse events were manageable with dose interruptions, reductions, and supportive care. No new safety signals were reported on longer follow‑up.
Clinical interpretation and implications
These two complementary reports from TALAPRO‑2 support several practical points for clinicians:
- Combination talazoparib plus enzalutamide is an effective initial treatment option for mCRPC, delivering both rPFS and OS advantages.
- The magnitude of benefit is greatest in patients with HRR alterations, particularly BRCA1/2; these patients should be prioritized for genomic testing at or before transition to castration‑resistant disease.
- Even in unselected populations, a modest OS benefit was observed, likely driven by the HRR‑deficient subgroup. This finding raises the question of whether broader use is appropriate or whether biomarker‑guided selection remains preferable to maximize benefit and limit toxicity.
- Hematologic toxicity is common and requires proactive monitoring and dose management strategies. Centers must be prepared for frequent blood count surveillance and supportive interventions (transfusion, growth factors as appropriate per guidelines).
Strengths, limitations, and remaining questions
Strengths of the data include randomized double‑blind design for talazoparib allocation, prospective HRR testing in the dedicated cohort, long median follow‑up, central blinded rPFS assessment, and alpha‑protected OS analyses.
Limitations and open issues:
- Cross‑trial and cross‑setting comparisons are imperfect: prior post‑PARP/ARPI sequencing patterns and subsequent therapies may influence OS differences.
- Although the unselected cohort showed an overall OS benefit, benefit magnitude varied by HRR status; the net clinical benefit in HRR‑non‑deficient patients remains less certain.
- High rates of grade ≥3 anemia may limit tolerability in frail patients and could affect real‑world uptake without robust supportive care pathways.
- Biomarker heterogeneity beyond BRCA (e.g., non‑BRCA HRR genes) requires further interrogation to refine selection and understand drivers of benefit.
Practical recommendations and future directions
For practicing clinicians managing mCRPC:
- Offer comprehensive tumour (or circulating tumour DNA) HRR gene testing early in the course of advanced prostate cancer care to identify BRCA1/2 and other HRR alterations.
- Consider talazoparib plus enzalutamide as a standard initial option for patients with HRR‑deficient mCRPC, with particular enthusiasm for BRCA‑altered disease.
- Implement proactive hematologic monitoring and dose modification algorithms; discuss transfusion and growth factor use per institutional practice.
Research priorities include dissecting which non‑BRCA HRR alterations confer meaningful benefit, optimizing sequencing with chemotherapy and other targeted agents (including PSMA‑targeted therapies), and evaluating quality‑of‑life tradeoffs in real‑world settings.
Conclusion
The final TALAPRO‑2 results provide high‑quality randomized evidence that talazoparib combined with enzalutamide prolongs overall survival and rPFS in mCRPC, with the most compelling effect seen in BRCA1/2‑altered tumours. These data support genomic testing and biomarker‑driven use of PARP inhibitor combinations in routine care, while highlighting the need to manage hematologic toxicity and to refine patient selection for maximal benefit.
Funding and trial registration
Funding: Pfizer. ClinicalTrials.gov: NCT03395197.
Key references
Fizazi K, Azad AA, Matsubara N, et al. Talazoparib plus enzalutamide in men with HRR‑deficient metastatic castration‑resistant prostate cancer: final overall survival results from the randomised, placebo‑controlled, phase 3 TALAPRO‑2 trial. Lancet. 2025 Aug 2;406(10502):461‑474. doi:10.1016/S0140‑6736(25)00683‑X.
Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with metastatic castration‑resistant prostate cancer: final overall survival results from the randomised, placebo‑controlled, phase 3 TALAPRO‑2 trial. Lancet. 2025 Aug 2;406(10502):447‑460. doi:10.1016/S0140‑6736(25)00684‑1.
