Could upfront PARP inhibition transform outcomes for patients with HRR-altered metastatic hormone-sensitive prostate cancer? New data from the landmark TALAPRO-3 trial show meaningful rPFS gains with talazoparib plus enzalutamide, reinforcing the importance of early biomarker testing.
touchONCOLOGY coverage of ASCO 2026
In this Q&A, principal investigator Dr Neeraj Agarwal (Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA) discusses the important findings from the landmark phase 3 TALAPRO-3 trial (NCT04821622), presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago. The study showed that adding the PARP inhibitor talazoparib to the ARPI enzalutamide significantly improved radiographic progression-free survival in patients with homologous recombination repair-altered metastatic hormone-sensitive prostate cancer, with benefit seen across both BRCA and non-BRCA subgroups. In the discussion below, Dr Agarwal explores the implications for frontline treatment, quality of life, toxicity management and the growing importance of genomic and germline testing.
→ Abstract LBA5007: 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: ASCO, Chicago, IL, USA. May 29 to June 2, 2026.
Transcript:
Hi, my name is Dr Neeraj Agarwal. I’m a medical oncologist focusing on genitourinary cancers, particularly prostate cancer, and I’m Professor of Medicine and Medical Oncology at the Huntsman Cancer Institute at the University of Utah in Salt Lake City, United States.
Background (0:24)
I presented the TALAPRO-3 trial, and we simultaneously published the paper in the New England Journal of Medicine. These are really exciting data. To give some background, previously in the phase 3 TALAPRO-2 trial, we showed that the combination of a PARP inhibitor plus an ARPI significantly improved radiographic progression-free survival (rPFS) and overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC), with the greatest benefit seen in patients with homologous recombination repair (HRR) gene-altered mCRPC.
From the BRCAAway trial, we also previously showed that if you combine these two agents, they are more efficacious than either agent alone or when they are sequenced. Even though it was an investigator-initiated trial, the signal was quite clear that combination therapy may be more effective than sequencing.
We also know that patients with metastatic hormone-sensitive prostate cancer (mHSPC), which is the newly diagnosed metastatic prostate cancer setting — now also referred to as androgen pathway-modulation-sensitive metastatic prostate cancer (APMS) — and who have HRR gene alterations tend to have a poorer prognosis. They may not respond as well to current therapies, and once they progress, the disease can become even more aggressive. Taking all of this rationale together, we decided to test the combination of talazoparib plus enzalutamide — a PARP inhibitor plus an ARPI — in the upfront setting.
Trial design and eligibility criteria (2:04)
The patient population included those with metastatic HSPC, or APMS disease, who had HRR gene alterations. They were randomized 1:1 to receive talazoparib 0.5 mg plus enzalutamide 160 mg once daily, or placebo plus enzalutamide 160 mg once daily. Randomization was stratified by standard factors we often use, such as de novo versus relapsed disease, high-volume versus low-volume disease, and BRCA mutation-positive versus non-BRCA mutation-positive patients. Radiographic progression-free survival (rPFS) was the primary endpoint, and overall survival was a key secondary endpoint, alpha-protected, meaning the trial was powered to assess overall survival if rPFS was positive.
Efficacy results (3:07)
Now let’s look at the results. First, if you look at the baseline demographics, we did not see over-representation of any subgroup. It was a generalisable representation of patients with mHSPC and HRR gene alterations. Thirty-five percent of patients had BRCA mutations. Other common mutations, such as ATM, were present in about 30% of patients, and CDK12 mutations were present in about 20%. So this was pretty representative of what we see in the clinic.
Looking at radiographic progression-free survival, which was the primary endpoint, treatment with talazoparib plus enzalutamide significantly improved rPFS, reducing the risk of disease progression or death by 52%. That’s quite remarkable, especially considering the active enzalutamide control arm, which itself achieved an rPFS of 45.8 months. To build on such an active control is highly meaningful. The hazard ratio was 0.48. If you look at rPFS in BRCA-mutated versus non-BRCA-mutated patients, the hazard ratio was 0.37 in the BRCA-mutated group, meaning a 63% reduction in the risk of progression or death. Even in the non-BRCA-mutated group, there was a 43% reduction in risk. Fortunately, most patients have still not progressed and are alive, so the overall survival data remain immature. However, the hazard ratio is currently 0.77, favouring the combination, and we hope to show more mature overall survival data in the near future.
Looking at other gene mutations, such as ATM and CDK12, we saw a hazard ratio of 0.48 in ATM-mutated patients and a hazard ratio of 0.27 in patients with CDK12-mutated disease. That’s quite striking. So again, there was benefit across the board. This also brings me to quality of life. Before that, I should mention that time to PSA progression and time to subsequent anti-neoplastic therapy were also improved, with hazard ratios of around 0.5 — almost a 50% reduction in the risk of PSA progression or the need for next-line therapy such as chemotherapy. These are meaningful outcomes for our patients. If you look at quality of life, it was maintained. We used standard quality-of-life measures and saw no compromise across global health status, physical functioning, or role functioning. There was some slight deterioration in appetite loss on the EORTC QLQ-C30 — quite a mouthful — but these are standardized scales, and other than that, quality of life was maintained. To me, that tells us that the increased efficacy is offsetting the impact of treatment-related side effects.
Tolerability data (6:27)
That brings me to side effects. Seventy-nine percent of patients in the combination arm had grade 3/4 treatment-emergent adverse events, compared with 41% in the ADT plus enzalutamide arm. The side-effect profile was largely dominated by anemia.Before going deeper into anemia, I’d like to highlight that nausea, vomiting, gastrointestinal side effects, and grade 3 fatigue were all seen at low frequencies, mostly in the single digits, and I think that’s reflected in the quality-of-life data.
Looking specifically at anemia, it was present before starting treatment in 43% of patients. Grade 3/4 anemia occurred early on, with a median time to onset of around 3 months. After 13 weeks, the incidence declined. This tells us that anemia is an early event rather than a cumulative toxicity. Importantly, the protocol required mandatory dose reduction after grade 3/4 anemia. Once the dose was reduced, patients were generally able to tolerate treatment and remain on therapy, as evidenced by the median duration of talazoparib treatment being similar — 34 months versus 36 months — in patients who did and did not experience grade 3/4 anemia. So the key is to monitor patients closely early on, ideally every month. In those who appear to be on a trajectory to develop grade 3/4 anemia, we can reduce the dose pre-emptively rather than waiting for severe anemia to occur. In real-world clinical practice, I think we can do that. We don’t have to follow a protocol requiring grade 3/4 anemia before reducing the dose. I would also definitely check vitamin D, vitamin B12, folate, and iron levels to help reduce the incidence of anemia. Overall, only 5% of patients had to discontinue talazoparib because of grade 3/4 anemia.
Conclusions (8:35)
To conclude, this is a very effective combination. It significantly improves rPFS and meaningfully reduces the risk of progression and death in both BRCA-mutated and non-BRCA-mutated subgroups. It delays PSA progression, delays chemotherapy, and overall survival is trending in the right direction. Importantly, all of this is achieved without compromising quality of life. These data make next-generation sequencing (NGS) and germline testing in our patients more critical than ever.
Disclosures: Neeraj Agarwal has received research funding from: Amgen (Inst); Arvinas (Inst); AstraZeneca (Inst); Bayer (Inst); Bristol-Myers Squibb (Inst); Calithera Biosciences (Inst); Celldex (Inst); crispr therapeutics (Inst); Eisai (Inst); Exelixis (Inst); Genentech (Inst); Gilead Sciences (Inst); Immunomedics (Inst); Janssen (Inst); Lilly (Inst); Merck (Inst); Nektar (Inst); ORIC Pharmaceuticals (Inst); ORIC Pharmaceuticals (Inst); Pfizer (Inst); Takeda (Inst). He has received travel, accommodations and expenses from: Exelixis; Pfizer.
This content has been developed independently by Touch Medical Media for touchONCOLOGY. It is not affiliated with the American Society of Clinical Oncology. Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.
Cite: Upfront PARP inhibition in mHSPC: Key findings from TALAPRO-3 trial. TouchONCOLOGY. 22nd June 2026.
Editor: Sophie Nickelson
