Integrating Talazoparib Plus Enzalutamide Into HRR-Mutated mHSPC Care

Treatment intensification has become central to care for patients with metastatic hormone-sensitive prostate cancer (HSPC). Results from the phase 3 TALAPRO-3 trial (NCT04821622) may add a biomarker-driven option for patients whose tumors harbor homologous recombination repair (HRR) gene alterations. In the trial, adding talazoparib (Talzenna) to enzalutamide (Xtandi) plus androgen deprivation therapy (ADT) reduced the risk of radiographic progression or death by 52% vs placebo plus enzalutamide (HR, 0.48; 95% CI, 0.36-0.65; P <.001).¹

CancerNetwork® spoke with Neal D. Shore, MD, FACS, medical director of the Carolina Urologic Research Center and primary investigator of the TALAPRO-3 trial, about the study’s findings and what they mean for clinical practice.

Shore began by interpreting the magnitude of benefit in patients with BRCA1/2 alterations vs other HRR alterations. He then outlined best practices for genetic testing, monitoring, and dose modifications across urology, medical oncology, and advanced practice teams. Next, he discussed which patient subgroups derived the greatest benefit from the combination and described workflows to speed up germline and somatic testing. He concluded by explaining how a potential FDA approval could affect treatment sequencing in an increasingly crowded metastatic HSPC landscape.

CancerNetwork: Given that the TALAPRO-3 trial demonstrated a 52% reduction in the risk of radiographic progression or death in the overall HRR-mutated population, how do you interpret the magnitude of benefit in the BRCA1/2-mutated cohort vs the non-BRCA HRR-altered cohort?

Shore: Looking at the primary end point, investigator-assessed rPFS [radiographic progression-free survival], there is an HR of 0.48 in the intent-to-treat population, which is the 52% reduction you allude to. That is incredibly impressive. When you break it down and delineate the BRCA1/2 group, where the overwhelming majority were BRCA2, that HR goes from 0.48 to [0.37]. In the non-BRCA group, it goes up only slightly, from 0.48 to [0.57]. That is a very powerful clinical impact.

When you look at the Kaplan-Meier curves for the intent-to-treat population, and for the BRCA subgroup vs the non-BRCA subgroup, the curves separate very early, within a matter of a few months. That is remarkably impactful in terms of showing efficacy against progression for these patients. The demographics are also important: 70% of these patients had high-volume disease based on CHAARTED criteria.

From a practical care delivery perspective, what best practices do you recommend for monitoring, dose modifications, and supportive care to maintain treatment intensity while ensuring quality of life in this earlier disease setting?

[T]here are a lot of different issues to address, and they may be a little different if you are a urologist, a medical oncologist, or an advanced practice provider. But let us assume you are a health care provider in any one of those 3 groups. You want to optimize your patient care and your conversations with patients and their caregivers about [metastatic] HSPC, or—as Prostate Cancer Working Group 4 renamed it—androgen pathway modulation–sensitive disease.

First and foremost, you have to do genetic testing on these patients; it is in all the guidelines. Anybody with [metastatic] HSPC, whether it is de novo or recurrent [that is, synchronous or metachronous], should have germline genetic testing. About 10% of these patients will have a positive pathogenic variant, and of that 10%, about a third are going to be BRCA. You cannot stop there, though. If you do only germline testing and not somatic testing, you would miss another 50% of patients in whom you could pick up HRR alterations.

In my practice, all of my patients with metastatic disease get germline and somatic testing, whether their disease is de novo or recurrent, high volume or low volume. I prefer tissue for somatic testing. If I cannot get tissue, I will do blood-based somatic testing, because that is how you pick up more of these HRR alterations, and we have the list from TALAPRO-3.

Once a patient has one of the alterations within the TALAPRO-3 panel, you are going to have the important shared decision-making conversation with the patient and his caregiver team. You are also going to do monthly [complete blood counts (CBCs)], as you do for all PARP inhibitor therapies. You can talk with the patient about dose reduction if they have any concerns about adverse events [AEs]. The most common might be some GI [gastrointestinal] intolerability, which is very manageable with dose reduction. The myelosuppressive events are also very manageable, with both dose reduction and dose interruption.

When you first start patients on treatment, these types of AEs, whether grade 1, grade 2, or occasionally grade 3, happen fairly early, within the first 1 to 3 months. It is fairly uncommon to see them later. But it is still always important to evaluate the marrow regularly with CBCs, even if patients are not having problems early on.

Considering the increased rate of high-grade treatment-emergent AEs compared with enzalutamide monotherapy, which patient subpopulations or fitness profiles in the castration-sensitive setting stand to gain the greatest net clinical benefit from this intensified combination?

Consider the data we presented and published in The New England Journal of Medicine, and our subgroup analyses. Let me start with the forest plot by BRCA vs non-BRCA status: there is clear benefit. By disease volume, there is tremendous benefit in the high-volume group, and still a benefit in the low-volume group, although the confidence interval crosses 1. So anyone with the gene alterations in our panel who has high-volume disease clearly benefits.

By age, patients younger than 70 years and those 70 years or older had equal benefit. Patients benefited greatly whether they had bone-only disease, soft tissue disease, or both bone and soft tissue disease. They also benefited regardless of Gleason score, grade group 4 and higher or lower than grade group 4; all performance status groups had equal benefit. That to me is remarkably impressive. Patients benefited whether or not they had received an [androgen receptor pathway inhibitor (ARPI)] before enrolling in the study, although the numbers with prior ARPI exposure were a little small.

The gene-by-gene subgroup analysis is also impressive. What really impressed me was how well patients with ATM alterations did, because [they] typically do not do well in our resistant-biology trials. Patients with BRCA alterations clearly did well, and patients with CDK12 alterations did remarkably well. For some of the less common genes that are seen very infrequently, such as FANCA and MLH1, the numbers are so small that you cannot draw any conclusions.

What practical strategies or workflows can care teams implement to eliminate testing bottlenecks, reduce turnaround times, and ensure no eligible patient misses the window for upfront biomarker-driven combination therapy?

It should be protocol that 100% of your patients with metastatic prostate cancer get germline testing. Full stop. No exceptions. That matters because you now have an opportunity to dramatically intensify and optimize their therapy by offering the triplet of talazoparib with enzalutamide and ADT. The alternatives are just ADT and enzalutamide alone, or another ADT and ARPI doublet alone. There is no doubt.

Germline testing is also really important for informing families through cascade testing. We did not look at that in the trial, but we are all health care providers; if a patient has a germline pathogenic variant, you want to inform family members. That way, cancers such as breast…, pancreatic, ovarian, or prostate cancer could potentially be discovered when they are localized and not metastatic.

There should be an absolute pathway for anybody who treats metastatic prostate cancer. I am going to focus on that setting because it is what we looked at in TALAPRO-3—I certainly have separate opinions on high-risk localized disease. That protocol should mandate that everybody gets germline testing, through blood work or a buccal mucosal swab. It should also require that a sample, preferably the prostate biopsy, gets sent for somatic testing. Doing both up front will improve your turnaround time, and you will get both results relatively quickly. If you have insufficient tissue, for example because the patient came to you from another location, then you can at least do liquid-based testing. Those reports usually come back a little faster, which also helps turnaround times.

Upfront biomarker-driven decision-making is state-of-the-art, and patients appreciate that. If you are diagnosing, evaluating, and managing these patients, look into your own internal processes to make sure germline and somatic testing are done efficiently and rapidly.

If the FDA approves this combination, how will your approach to subsequent lines of therapy, such as chemotherapy or radioligand therapy, when patients eventually progress on frontline talazoparib and enzalutamide, be affected?

It is a great question because we now have an embarrassment of riches. We have 4 doublets for our patients with androgen pathway modulation–sensitive disease:

ADT with abiraterone acetate [Zytiga] and prednisone

1. ADT with enzalutamide
2. ADT with apalutamide [Erleada]
3. ADT with darolutamide [Nubeqa]

We also have 2 taxane-based therapies. Docetaxel is the only taxane approved in patients with high-volume [metastatic] HSPC; cabazitaxel [Jevtana] is available once patients develop resistant biology. In addition, the [phase 3 PEACE-1 (NCT01957436)] and [phase 3 ARASENS (NCT02799602)] trials demonstrated the triplets of ADT, abiraterone, and docetaxel, and of ADT, darolutamide, and docetaxel, respectively.^2,3 I typically reserve those for patients with liver metastases or very high-volume bone metastases with a lot of symptoms. I would certainly view those cases differently if the patients had HRR mutations, from the panel we looked at in TALAPRO-3.

Most recently, we also had the US approval based on the CAPItello-281 trial [NCT04493853].That trial compared ADT plus capivasertib [Truqap] and abiraterone with prednisone vs ADT and abiraterone. The combination is particularly beneficial for patients who have PTEN deficiency by IHC [immunohistochemistry].⁴ We also have the recent approval based on the PSMAddition trial [NCT04720157], which added lutetium Lu 177 vipivotide tetraxetan [Pluvicto] for 6 cycles to ADT and an ARPI.⁵

Baked into the question, it is going to be important that our colleagues recognize the full range of options. There are 4 doublets, a taxane, and now 3 more triplets, if you count ADT/abiraterone/capivasertib and ADT/ARPI/lutetium-617. There are also now 2 PARP inhibitor triplets: ADT, abiraterone, and niraparib [Zejula] from the earlier [phase 3 AMPLITUDE trial (NCT04497844)], and now ADT, enzalutamide, and talazoparib from TALAPRO-3.⁶

One of the most important points is that fewer than 10% of patients with this type of metastatic HSPC should receive ADT monotherapy, across the overall population. Yet real-world data tell us that perhaps 25% to 40% of patients are still receiving ADT monotherapy. That is an area where we have to do so much better.

If patients receive the triplet of ADT, talazoparib, and enzalutamide and ultimately progress, I am going to look at their concomitant medications, other comorbidities, tumor burden, and performance status. But once they develop resistant biology, my options could certainly still include taxane-based therapy or radiopharmaceutical therapies. I certainly would not switch to another ARPI, which happens far too often. We want to make sure we continue to offer patients novel mechanisms of action when making treatment decisions at progression.

References

1. Agarwal N, Matsubara N, Azad AA, et al. PARP and androgen-signaling inhibition plus ADT in metastatic prostate cancer. N Engl J Med. 2026;395:427-439. doi:10.1056/NEJMoa2604126
2. Gravis Mescam G, Maldonado X, Roubaud G, et al. 8-month PSA strongly predicts outcomes of men with metastatic castration-sensitive prostate cancer in the PEACE-1 phase III trial. Ann Oncol. 2022;33(suppl 7):1361MO. doi:10.1016/annonc/annonc1070
3. Carles J, Tombal B, Hussain M, et al. Age-related efficacy and safety of darolutamide plus androgen-deprivation therapy and docetaxel in patients with metastatic hormone-sensitive prostate cancer: a subgroup analysis of the phase 3 ARASENS trial. Eur Urol Oncol. 2025;S2588-9311(25)00255-X. doi:10.1016/j.euo.2025.10.001
4. Truqap combination approved in the US as first and only targeted treatment for PTEN-deficient metastatic hormone-sensitive prostate cancer. News release. AstraZeneca. June 12, 2026. Accessed September 28, 2026. https://tinyurl.com/3mwyj5aj
5. FDA approves lutetium Lu 177 vipivotide tetraxetan with androgen receptor pathway inhibitor therapy for metastatic androgen pathway modulation-naïve or -sensitive prostate cancer. FDA. July 31, 2026. Accessed September 28, 2026. https://tinyurl.com/4xzv5cyw
6. Attard G, Agarwal N, Graff JN, et al. Niraparib and abiraterone acetate plus prednisone for HRR-deficient metastatic castration-sensitive prostate cancer: a randomized phase 3 trial. Nat Med. 2025;31:4109-4118. doi:10.1038/s41591-025-03961-8