TALAPRO-3 Shows Talazoparib Plus Enzalutamide Improves rPFS in HRR-Altered mCSPC

The combination of talazoparib (Talzenna) and enzalutamide (Xtandi) led to a 52% reduction in the risk of radiographic progression or death vs placebo plus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCSPC) harboring homologous recombination repair (HRR) gene alterations, according to data from the phase 3 TALAPRO-3 trial (NCT04821622) presented at the 2026 ASCO Annual Meeting.^1,2

At a median follow-up of 37.6 and 37.7 months in the respective arms, the median radiographic progression-free survival (rPFS) by investigator assessment was not reached (NR; 95% CI, NR-NR) with talazoparib plus enzalutamide (n = 300) vs 45.8 months (95% CI, 37.7-NR) with placebo plus enzalutamide (n = 299; HR, 0.481; 95% CI, 0.357-0.647; P < .0001). The 36-month rPFS rates were 76.6% (95% CI, 70.8%-81.4%) and 56.2% (95% CI, 50.0%-62.0%), respectively, with 67 and 126 rPFS events recorded.

“These results support talazoparib plus enzalutamide as a potential treatment option for patients with HRR gene–altered mCSPC, and early molecular testing is critically important in these patients,” said lead study author Neeraj Agarwal, MD, FASCO, in a presentation of the data. Agarwal is a professor and presidential endowed chair of cancer research at the Huntsman Cancer Institute, University of Utah, in Salt Lake City.

Why do the TALAPRO-3 data matter for HRR gene-altered mCSPC?

HRR gene alterations occur in approximately 23% of patients with prostate cancer and are associated with worse outcomes.^3,4 Despite treatment intensification with androgen deprivation therapy (ADT) plus androgen receptor pathway inhibitors (ARPIs) in mCSPC, outcomes for patients with HRR gene alterations remain suboptimal, underscoring an unmet need for improved approaches earlier in the disease course.⁴

The combination of a PARP inhibitor and an ARPI has previously demonstrated activity in later-line disease. In the phase 3 TALAPRO-2 trial (NCT03395197), the addition of talazoparib to enzalutamide resulted in significantly prolonged rPFS and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC), with the greatest benefit observed in HRR gene-altered disease.⁵

TALAPRO-3 was designed to examine whether moving the combination earlier, into the castration-sensitive setting, would improve efficacy compared with enzalutamide alone in patients with HRR gene-altered mCSPC undergoing ADT.

How was the TALAPRO-3 trial designed?

TALAPRO-3 is a phase 3, randomized, double-blind, placebo-controlled trial that enrolled 599 patients with HRR gene-altered mCSPC, an ECOG performance status no higher than 1, and metastatic disease confirmed by bone scan or by CT or MRI. Patients were required to be on ongoing ADT and to have received no more than 3 months of prior ADT with or without an ARPI for mCSPC. Those with prior exposure to docetaxel for mCSPC were excluded. Eligible HRR genes included ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C.

Patients were randomly assigned 1:1 to receive talazoparib at a dose of 0.5 mg plus enzalutamide at 160 mg once daily or placebo plus enzalutamide at 160 mg once daily. Randomization was stratified by de novo vs relapsed mCSPC, high- vs low-volume disease, and BRCA-mutated vs non–BRCA-mutated status. The primary end point was investigator-assessed rPFS, and OS was an alpha-protected key secondary end point that was tested only if rPFS was determined to be significant.

At the data cutoff date of February 18, 2026, baseline characteristics were well balanced, according to Agarwal. The median patient age was 69.5 years (range, 44-89), the median prostate-specific antigen (PSA) level was 3.6 ng/mL (range, 0-2282), and 34.5% of patients harbored BRCA1/2 mutations. Most patients in the talazoparib and placebo arms, respectively, had de novo disease (84% vs 85%), high disease volume (70% vs 71%), a Gleason score of at least 8 (82%; 82%), and an ECOG performance status of 0 (66%; 70%). Moreover, disease sites in the talazoparib arm included bone only (29%), soft tissue only (13%), and both (59%); in the placebo arm, these respective rates were 32%, 9%, and 58%.

In terms of HRR gene alterations, 35% of those in the talazoparib arm had BRCA1/2 mutations vs 34% of those in the placebo arm; 65% and 66% of patients, respectively, had other. The tissue source for HRR gene alteration testing was both the tissue and the blood for most patients (68% vs 71%). In the talazoparib arm, 29% of patients had at least 1 ATM mutation in the corresponding HRR gene, as did 29% for BRCA2, 18% for CDK12, and 15% for CHEK2; in the placebo arm, these respective rates were 27%, 31%, 20%, and 15%.

What were the additional efficacy outcomes with talazoparib plus enzalutamide?

The rPFS benefit was observed in both biomarker-defined subgroups. In patients with BRCA1/2 alterations, talazoparib plus enzalutamide reduced the risk of radiographic progression or death by about 63% (HR, 0.368; 95% CI, 0.222-0.609; P < .0001); in the non–BRCA-mutated HRR subgroup, the reduction was approximately 43% (HR, 0.567; 95% CI, 0.392-0.819; P = .0022).

A consistent treatment effect favoring the combination was seen across prespecified subgroups, and in post hoc by-gene analyses, rPFS generally favored talazoparib plus enzalutamide across HRR gene subgroups, including ATM and CDK12; formal analyses were limited in several rare subgroups by small numbers, Agarwal noted.

Interim OS data were immature but trended in favor of the combination (74 vs 91 deaths; HR, 0.767; 95% CI, 0.564-1.044; P = .0905). Time to PSA progression favored the combination, with an approximate 49% reduction in risk (HR, 0.513; 95% CI, 0.370-0.712; P < .0001), as did time to subsequent antineoplastic therapy (HR, 0.514; 95% CI, 0.378-0.698; P < .0001). Docetaxel was the most common subsequent antineoplastic therapy in both arms (45% vs 58%); 9% vs 27% of patients received olaparib (Lynparza).

Moreover, the objective response rate was 74.7% (95% CI, 64.8%-82.7%) with the combination vs 67.0% (95% CI, 57.2%-75.5%) with placebo plus enzalutamide (P = .2925). In the respective arms, the median duration of response was not reached vs 27.2 months (95% CI, 19.5-39.6).

What did the safety analysis of talazoparib plus enzalutamide show?

In the safety population, grade 3/4 treatment-emergent adverse effects (TEAEs) occurred in 79% vs 41% of patients in the talazoparib (n = 299) and placebo (n = 295) arms, respectively, and serious adverse effects (AEs) occurred in 42% vs 32%. Grade 5 TEAEs were reported in 3% of patients in each arm and included 2 treatment-related deaths in the combination arm (1 from pancytopenia and 1 from worsening idiopathic pulmonary fibrosis) and none in the control arm.

AEs led to permanent discontinuation of talazoparib or placebo in 19% vs 10% of patients, respectively. In the talazoparib arm, AEs led to dose interruption of talazoparib for 69% of patients and enzalutamide for 47% of patients; AEs led to dose reduction of talazoparib for 60% of patients and of enzalutamide for 18% of patients.

The most common all-grade TEAEs in the combination arm were anemia (71%), fatigue (28%), and decreased neutrophil count (27%); in the placebo arm, they were hot flush (23%), arthralgia (23%), hypertension (22%), and anemia (22%). AEs of special interest included myelodysplastic syndrome in 3 patients in the combination arm vs 1 patient in the control arm, acute myeloid leukemia in 2 vs 0 patients, and venous embolic and thrombotic events in 7 vs 5 patients.

Because anemia was common, investigators characterized it further. At baseline, 43% of patients in the combination arm had grade 1/2 anemia; the median time to onset was 3.2 months, and incidence declined after the first 3 months. Forty percent of patients received a packed red blood cell transfusion. The median duration of talazoparib treatment was comparable between patients who developed grade 3/4 anemia and those who did not (34.2 vs 35.9 months), and only 5% of patients permanently discontinued talazoparib because of anemia.

What did the analysis of patient-reported outcomes reveal about talazoparib?

No clinically meaningful differences in patient-reported outcomes were observed between the arms, with the exception of appetite loss (5.2; 95% CI, 2.5-8.0) per the EORTC QLQ-C30.

Disclosures: Agarwal reported receiving research funding (paid to his institution) from Amgen, Arvinas, AstraZeneca, Bayer, Bristol-Myers Squibb, Calithera Biosciences, Celldex, Crispr Therapeutics, Eisai, Exelixis, Genentech, Gilead Sciences, Immunomedics, Janssen, Lilly, Merck, Nektar, ORIC Pharmaceuticals, Pfizer, and Takeda; and travel expenses from Exelixis and Pfizer.

References

1. Agarwal N, Matsubara N, Azad AA, et al. TALAPRO-3: talazoparib (TALA) + enzalutamide (ENZA) compared with placebo (PBO) + ENZA for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC) harboring homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2026;44(suppl 17):LBA5007. doi:10.1200/JCO.2026.44.17_suppl.LBA5007
2. Agarwal N, Matsubara N, Azad AA, et al. PARP and androgen-signaling inhibition plus ADT in metastatic prostate cancer. N Engl J Med. Published online May 30, 2026. doi:10.1056/NEJMoa2604126
3. Chung JH, Dewal N, Sokol E, et al. Prospective comprehensive genomic profiling of primary and metastatic prostate tumors. JCO Precis Oncol. 2019;3:1-23. doi:10.1200/PO.18.00283
4. Olmos D, Lorente D, Jambrina A, et al. BRCA1/2 and homologous recombination repair alterations in high- and low-volume metastatic hormone-sensitive prostate cancer: prevalence and impact on outcomes. Ann Oncol. 2025;36(10):1190-1202. doi:10.1016/j.annonc.2025.05.534
5. Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023;402(10398):291-303. doi:10.1016/S0140-6736(23)01055-3