Clinical Summary: 

• Design/Population: Phase 3 TALAPRO-3 trial randomizing 599 patients with newly diagnosed metastatic hormone-sensitive prostate cancer and prospectively confirmed HRR gene alterations to enzalutamide plus talazoparib or enzalutamide plus placebo, both combined with androgen deprivation therapy.
• Key Outcomes: Talazoparib plus enzalutamide reduced the risk of radiographic progression or death by 52%, with benefits observed in both BRCA-mutated and non-BRCA HRR-altered populations. Significant improvements were also seen in time to PSA progression, castration resistance, and subsequent antineoplastic therapy, while quality of life was maintained.
• Clinical Relevance: These findings support earlier integration of PARP inhibition in HRR-altered metastatic hormone-sensitive prostate cancer and may establish talazoparib plus enzalutamide as a new precision medicine–based treatment standard.

Neeraj Agarwal, MD, Huntsman Cancer Institute, Salt Lake City, Utah, discusses results from the phase 3 TALAPRO-3 trial evaluating talazoparib plus enzalutamide in patients with HRR-altered metastatic hormone-sensitive prostate cancer. The study builds on prior success of PARP inhibitor and androgen receptor pathway inhibitor combinations in metastatic castration-resistant disease and extends this strategy into the hormone-sensitive setting.

The combination significantly improved radiographic progression-free survival compared with enzalutamide alone, including among patients with non-BRCA alterations such as ATM and CDK12 mutations. Although anemia was the most common grade 3/4 adverse event, it was generally manageable with dose modification, allowing most patients to remain on therapy long term while preserving overall quality of life.

Dr Agarwal presented these results at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

Transcript: 

Hello, my name is Neeraj Agarwal, I’m a professor of medicine and medical oncology at the Huntsman Cancer Institute, University of Utah.

Let’s discuss the results of the TALAPRO-3 phase 3 trial in patients with metastatic hormone-sensitive prostate cancer, or what is now often referred to as androgen pathway inhibitor–sensitive metastatic prostate cancer, in patients with homologous recombination repair, or HRR, gene alterations. This was a large phase 3 randomized trial.

Before discussing the trial design and results, I’d like to provide some background. We already knew from multiple studies in metastatic castration-resistant prostate cancer, or androgen pathway inhibitor–resistant prostate cancer, that combinations of androgen receptor pathway inhibitors and PARP inhibitors are effective. In the TALAPRO-2 trial, we previously showed that the combination of enzalutamide plus talazoparib improved overall survival compared with enzalutamide alone, not only in patients with HRR gene alterations but also in patients who were unselected for HRR alterations. However, the magnitude of benefit was clearly greater in patients with HRR gene alterations. As enzalutamide moved into the newly diagnosed metastatic prostate cancer setting, it became a logical next step to evaluate this combination in metastatic hormone-sensitive disease. 

In this study, 599 patients with newly diagnosed metastatic prostate cancer and prospectively confirmed HRR gene alterations were randomized to receive enzalutamide plus talazoparib or enzalutamide plus placebo. All patients were receiving androgen deprivation therapy. Radiographic progression-free survival was the primary end point, and overall survival was the key alpha-protected secondary end point, meaning the study was powered to evaluate overall survival if the primary end point was positive. Randomization was stratified by de novo versus recurrent disease, high-volume versus low-volume disease, and BRCA versus non-BRCA HRR gene alterations.

Looking at the results, there was a statistically significant and clinically meaningful improvement in radiographic progression-free survival. The hazard ratio was 0.48, representing a 52% reduction in the risk of progression or death with talazoparib plus enzalutamide. Median radiographic progression-free survival in the enzalutamide-alone arm was 45.8 months, which is already very impressive and reflects the efficacy of enzalutamide in metastatic hormone-sensitive prostate cancer.

What is remarkable is that the combination was able to significantly improve upon such an active control arm. As expected, the benefit was particularly strong in patients with BRCA mutations, where the hazard ratio was 0.37. However, importantly, patients with non-BRCA HRR gene alterations also benefited, with a hazard ratio of 0.57, corresponding to a 43% reduction in risk of progression or death.

We also conducted post hoc analyses of specific HRR subgroups. In patients with ATM mutations, the hazard ratio was 0.48. In patients with CDK12 alterations, who are traditionally not considered highly responsive to PARP inhibition, the hazard ratio was 0.27. These are quite remarkable findings when compared with such an active control arm. 

Other clinically meaningful end points also favored the combination. Time to PSA progression, time to castration resistance, and time to subsequent antineoplastic therapy all showed significant improvements. For example, time to subsequent antineoplastic therapy showed a hazard ratio of 0.51, representing a 49% reduction in risk.

Overall survival data remain immature. Fortunately, patients are living longer, and there have been relatively few events so far. Although we cannot draw definitive conclusions yet, the current hazard ratio is 0.77, favoring the combination. This is certainly encouraging, and we look forward to future analyses.

A common question is whether adding a second drug affects quality of life. Patient-reported outcomes were assessed using validated EORTC questionnaires. Overall, quality of life was maintained. The only notable difference was a modest increase in appetite loss in the combination arm. Otherwise, quality-of-life measures remained largely similar. So patients were experiencing substantial delays in disease progression and PSA progression while maintaining their quality of life, which is very meaningful.

No discussion would be complete without reviewing safety. Grade 3/4 treatment-emergent adverse events occurred in 79% of patients in the combination arm compared with 41% in the enzalutamide-alone arm. The dominant toxicity was anemia. Grade 3/4 anemia occurred in 51% of patients. Other potentially quality-of-life–impacting toxicities, such as nausea, vomiting, and gastrointestinal adverse events, were relatively uncommon, with grade 3/4 events generally occurring in the single-digit range. 

Because anemia was the major toxicity, it is important to discuss its management. Notably, 43% of patients already had grade 1/2 anemia at baseline before treatment initiation. Grade 3 /4 anemia typically occurred early, with a median time to onset of approximately 3.2 months. After week 13, the incidence of new grade 3/4 anemia decreased substantially, indicating that this was not a cumulative toxicity. The protocol required dose reduction of talazoparib after the first occurrence of grade 3/4 anemia. Once dose adjustments were made, patients generally tolerated treatment well. Importantly, patients who developed grade 3/4 anemia were able to remain on therapy for a similar duration as those who did not. The median duration of talazoparib treatment was 34 months in patients who developed grade 3/4 anemia versus 36 months in those who did not. Despite prolonged exposure to therapy, only about 5% of patients required treatment discontinuation because of anemia.

The key practical message is that when starting talazoparib plus enzalutamide, hemoglobin levels should be monitored closely, particularly during the first 3 to 5 months. I would not recommend reducing the dose preemptively at baseline because approximately half of patients will never require dose reduction, and doing so could potentially compromise efficacy. Instead, check vitamin B12, folate, and iron levels before treatment to identify any preexisting contributors to anemia, monitor hemoglobin closely, and reduce the talazoparib dose when clinically indicated. With this approach, most patients can tolerate talazoparib for approximately 3 years while achieving clinically meaningful and statistically significant delays in disease progression, PSA progression, and the need for subsequent therapy, all without compromising quality of life. That is the key message from TALAPRO-3. Thank you.

Source: 

Agarwal N, Matsubara N, Azad A, et al. TALAPRO-3: Talazoparib (TALA) + enzalutamide (ENZA) compared with placebo (PBO) + ENZA for the treatment of patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) harboring homologous recombination repair (HRR) gene alterations. Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. LBA5007.