TALAPRO-3: Talazoparib Plus Enzalutamide More Than Halves the Risk of Progression in HRR-Mutated Metastatic Castration-Sensitive Prostate Cancer

KEY FINDINGS

• TALAPRO-3 is a randomized, double-blind, phase 3 trial in 599 patients with metastatic castration-sensitive prostate cancer (mCSPC) harbouring a homologous recombination repair (HRR) gene mutation.
• Talazoparib plus enzalutamide produced a 52% reduction in risk for radiographic progression-free survival (rPFS) compared with enzalutamide alone (HR 0.481; 95% CI 0.357-0.647; p < 0.0001).
• The risk reduction reached 63% in patients with BRCA1/2 mutations (HR 0.368) and 43% in non-BRCA HRR alterations (HR 0.567). Although overall survival data are not yet mature, a numerical trend favouring the combination was observed (HR 0.77).
• The results were published simultaneously in the New England Journal of Medicine (DOI: 10.1056/NEJMoa2604126).

Study Design and Background

The combination of talazoparib (a PARP inhibitor) with enzalutamide (an androgen receptor pathway inhibitor) had previously significantly prolonged radiographic progression-free survival and overall survival in metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial, with the most pronounced benefit in patients with HRR gene alterations. The combination was approved for patients with HRR-mutated mCRPC in June 2023.

TALAPRO-3 tests the same combination at a much earlier stage of disease, that is, in the castration-sensitive setting where androgen deprivation therapy (ADT) is still effective. The rationale: despite contemporary ADT plus ARPI intensification strategies, outcomes for mCSPC patients with HRR gene alterations remain inadequate, highlighting the need for more effective strategies earlier in the treatment course.

The trial enrolled patients receiving ADT with at least one HRR alteration on a 12-gene HRR panel, ECOG performance status 0-1 and radiographically confirmed metastatic disease. Patients could have received up to 3 months of prior ADT (± ARPI) for mCSPC; those with prior docetaxel were excluded. A total of 599 patients were randomized 1:1 to talazoparib 0.5 mg/day plus enzalutamide 160 mg/day or placebo plus enzalutamide 160 mg/day, both arms on a background of ADT. Stratification factors included de novo versus relapsed metastatic disease, high versus low volume disease and BRCA-mutated versus non-BRCA HRR alteration status.

The primary endpoint was investigator-assessed rPFS; overall survival (OS) was an alpha-protected key secondary endpoint that, under the hierarchical testing strategy, would only be formally tested if the primary endpoint was significant. Baseline characteristics were balanced between the arms: median age 70 and 69, BRCA1/2 alterations 35% and 34%, de novo metastatic disease 84% and 85%, high-volume disease 70% and 71%, and a Gleason score ≥ 8 in 82% in both arms.

Key Results

The primary endpoint was met: median rPFS was not reached in the talazoparib plus enzalutamide arm versus 45.8 months in the control arm (HR 0.481; 95% CI 0.357-0.647; p < 0.0001). At approximately month 36, rPFS rates were 76.6% in the combination arm and 56.2% in the control arm.

In a gene-level post-hoc analysis, the most pronounced benefit was seen with ATM alterations (HR 0.433), BRCA2 alterations (HR 0.353) and CDK12 alterations (HR 0.275); however, these subgroup analyses should be interpreted with caution given the small patient numbers.

Safety profile: Grade 3-4 treatment-related adverse events occurred in 79% of the combination arm and 41% of the control arm. The most frequent adverse event was anaemia (71% versus 22%). Forty per cent of patients required red blood cell transfusion; nevertheless, the median duration of talazoparib treatment was similar in patients who did and did not develop anaemia (34.2 versus 35.9 months). Permanent treatment discontinuation because of anaemia occurred in only 5% of patients. Myelodysplastic syndrome was reported in 3 patients in the combination arm and 1 in the control arm; acute myeloid leukaemia in 2 patients in the combination arm and none in the control arm. In patient-reported quality of life measures, no clinically meaningful difference was seen between the arms other than loss of appetite.

Implications for Clinical Practice

HRR gene alterations are seen in approximately 25% of metastatic prostate cancers and are associated with a worse prognosis and a poorer response to existing standard treatments. The TALAPRO-3 results show that talazoparib plus enzalutamide may provide meaningful benefit in the castration-sensitive stage of disease as well, beyond its approved indication in mCRPC.

These findings once again underline the importance of early molecular testing (HRR gene panel testing) in patients diagnosed with metastatic prostate cancer; treatment decisions can be shaped by the genomic profile from the earliest stage of disease. Pfizer has announced that it will share the results with global health authorities and evaluate a submission to expand the Talzenna indication to mCSPC. Overall survival data are not yet mature; the final OS analyses will clarify the full clinical value of the combination at this earlier stage.

From a practical standpoint, the increased rate of grade 3-4 anaemia (in particular the need for transfusion) means that patient selection and close haematological monitoring during treatment are important; the data nevertheless indicate that this toxicity is largely manageable with appropriate dose reduction and supportive care and does not meaningfully limit treatment duration.

Conclusion

TALAPRO-3 has shown that talazoparib plus enzalutamide provides a clinically meaningful and statistically robust improvement in radiographic progression-free survival compared with enzalutamide alone in patients with HRR-mutated metastatic castration-sensitive prostate cancer. The benefit was observed consistently in both BRCA-mutated and non-BRCA HRR subgroups. These results demonstrate the expanding role of early genomic testing and of targeted combination therapies at earlier points in the disease course in advanced prostate cancer.

Note: Overall survival data are not yet mature and final analyses are awaited. The regulatory approval process for the combination in the mCSPC indication is ongoing; the results presented in this article reflect current information based on trial/congress data and the NEJM publication.

References

1. Agarwal N, et al. TALAPRO-3: Talazoparib + Enzalutamide Compared with Placebo + Enzalutamide for the Treatment of Patients with mCSPC Harboring HRR Gene Alterations. ASCO GU 2026, Abstract LBA5007. UroToday, ASCO 2026 congress summary
2. Agarwal N, Matsubara N, et al. PARP and androgen-signaling inhibition plus ADT in metastatic prostate cancer. N Engl J Med. 2026. doi:10.1056/NEJMoa2604126.
3. Clarke H. Phase 3 TALAPRO-3 trial meets primary end point in HRR-mutated mCSPC. Urology Times, 19 March 2026
4. ClinicalTrials.gov. Study of Talazoparib With Enzalutamide in Men With DDR Gene Mutated mCSPC (TALAPRO-3). NCT04821622
5. Pfizer. TALZENNA Plus XTANDI Significantly Improves Radiographic Progression-Free Survival in Metastatic Prostate Cancer. Press release, 19 March 2026.