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
- ADT with enzalutamide
- ADT with apalutamide [Erleada]
- 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
- 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
- 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
- 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
- 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
- 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
- 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
