What Does TALAPRO-3 Mean for Frontline Treatment of HRR-Altered mHSPC?

Combining PARP inhibition with androgen receptor pathway inhibition (ARPI) has already improved outcomes for patients with homologous recombination repair (HRR)–altered metastatic castration-resistant prostate cancer. The phase 3 TALAPRO-3 trial (NCT04821622) evaluated moving that approach into the hormone-sensitive setting. Among 599 patients with HRR-altered metastatic hormone-sensitive prostate cancer (HSPC), talazoparib (Talzenna) plus enzalutamide (Xtandi) and 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 Neeraj Agarwal, MD, FASCO, medical oncologist and co-director of the Prostate Cancer Program at Dana-Farber Cancer Institute, Harvard Cancer Care Consortium, about the trial’s findings and their implications for practice. Agarwal presented the TALAPRO-3 results at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.

Agarwal began by breaking down the magnitude of benefit across BRCA-mutated and other HRR-altered subgroups. He then explained the rationale for moving the combination into the frontline setting rather than sequencing therapies. Next, he outlined proactive strategies for managing anemia and weighed the combination’s toxicity against its efficacy. He also discussed why germline and somatic testing should be non-negotiable at diagnosis, and concluded by describing his approach to subsequent therapy after progression.

CancerNetwork: What is the clinical rationale for moving combined PARP inhibition and [ARPIs] into the frontline castration-sensitive setting, rather than using PARP inhibitors sequentially upon progression to castration-resistant disease?

Agarwal: The question is why we tested the combination of talazoparib plus enzalutamide in newly diagnosed patients when it is already approved in later lines of therapy. That later setting is what we call castration-resistant, or now androgen pathway modulation-resistant prostate cancer.

First, we know that treatments that work in the castration-resistant setting do better when you move them to the upfront setting. We have seen that theme with ARPIs, with docetaxel chemotherapy, and with radioligand therapy. These treatments continue to move upstream, not only in prostate cancer but in multiple other cancer types. The [phase 3 TALAPRO-2 trial (NCT03395197)] showed an absolute 14-month improvement in overall survival in patients with metastatic castration-resistant, or androgen pathway modulation–resistant prostate cancer who had HRR mutations.² It was a logical step for us to think about moving this combination to the upfront setting.

Second, people ask about sequencing vs upfront combination. In the phase 2 BRCAAway trial (NCT03012321), we reported that the combination of a PARP inhibitor with an ARPI was better than either sequence: an ARPI followed by a PARP inhibitor, or a PARP inhibitor followed by an ARPI.³

Lastly, and most importantly, we lose a significant number of patients to disease when we allow the disease to progress. Not only in prostate cancer but across cancer types, we see that not all patients receive second- or third-line therapy. In fact, attrition can be up to 50%, depending on which study you are looking at. When we give the most effective therapy at the time of new diagnosis, we get the most value out of the effort and time that we and our patients are spending. That is how I would rationalize moving this combination upfront, and I am so glad we did.

In TALAPRO-3, grade 3 or 4 anemia was observed in more than 50% of patients receiving the combination. What proactive management and dose modification strategies do you recommend to help patients maintain quality of life and stay on therapy without frequent interruption?

Grade 3/4 anemia happened in half of the patients, early in the course of treatment; the median time to onset was about 3 months. Once the dose was reduced to the next level after grade 3/4 anemia occurred, patients were able to tolerate talazoparib well. Only 5% of patients ultimately discontinued talazoparib because of anemia. The median duration of talazoparib treatment was also similar in patients who did and did not experience grade 3/4 anemia, about 3 years in both groups. This is a very important piece of information. Grade 3/4 anemia happens early on, and when you reduce the dose in patients who develop it, they are able to tolerate talazoparib well and derive benefit.

Blood transfusions really do not need to happen in the real-world setting. There, we are not mandated by protocol to wait for grade 3/4 anemia before we alter treatment or take a break, as we are across trials, where we have less flexibility to modify the dose.

I start everyone at the full dose because I know many patients will never develop grade 3/4 anemia, and then I check hemoglobin levels every month locally. Patients do not even have to come to my clinic. If I see a patient whose hemoglobin is rapidly declining and is on track to develop grade 3/4 anemia, I do not necessarily wait for it to happen; I reduce the dose before reaching that point. That is the most important practice point I have for my colleagues.

Also, more than 40% of patients in the trial had grade 1 or 2 anemia at baseline. If a patient already has grade 1/2 anemia before starting treatment, I rule out other causes. A patient with cancer can have vitamin B12, folate, or iron deficiency, and a simple polyp in the colon can cause anemia that is made worse by cancer therapy. If somebody has anemia at baseline, I do an anemia workup to make sure there are no reversible causes, and then I start talazoparib. At the same time, I keep an eye on the trajectory of the hemoglobin level every 2 to 4 weeks; I do every 4 weeks. With those measures, the vast majority of our patients will never develop grade 3/4 anemia in real-world practice.

Considering the increased rate of high-grade treatment-emergent adverse effects [TEAEs] compared with enzalutamide monotherapy, how do you weigh the toxicity of this intensified combination against its efficacy in castration-sensitive disease?

The higher rate of [TEAEs] was dominated by grade 3/4 anemia. As I just discussed, that can be easily prevented with some real-world practice tips….

Beyond that, consider the [AEs] better known to affect quality of life, such as nausea, vomiting, other gastrointestinal [AEs], and fatigue. Most of those occurred in the single digits, and grade 3/4 nonhematologic [AEs] were also in the single digits. Overall, this [AE] profile is something oncologists as a group are very used to dealing with—tell me a cancer treatment that does not cause anemia to some degree. We know how to manage, tackle, and prevent anemia.

Beyond [AEs], the efficacy was striking. The control arm received enzalutamide, one of the most active drugs in prostate cancer treatment, and ADT plus enzalutamide was associated with a PFS of 46 months. Beating that control arm with a 52% reduction in the risk of progression or death is not only a statistically significant, but a very clinically meaningful improvement in outcomes.

When you delay disease progression in the hormone-sensitive, or androgen pathway modulation–sensitive, state, you avoid the castration-resistant state, which is characterized by pain, suffering, and fractures. Delaying that symptomatic, lethal state of prostate cancer by the striking magnitude reflected in the HR of 0.48 is very clinically meaningful. That is how we can justify using the combination in hormone-sensitive, or androgen pathway modulation–sensitive, prostate cancer.

While somatic and germline testing are standard in castration-resistant disease, real-world testing rates in earlier-stage disease remain variable. How should community oncologists adapt their biomarker testing workflows at the initial castration-sensitive diagnosis to ensure eligible patients are identified early?

I will make it very simple: anyone with metastatic prostate cancer we are seeing for the first time deserves germline testing and somatic tumor tissue testing. It is no longer an option. These test results have implications not only for patients’ lives but potentially for the lives of their children, siblings, and extended family members.

This is not only about HRR mutations. We have other alterations, for example, MSI [microsatellite instability]–high and TMB [tumor mutational burden]–high states, which respond beautifully to immunotherapy. We have also just seen PTEN loss; PTEN loss detected by NGS [next-generation sequencing] may prompt immunohistochemistry testing, which may make patients candidates for other treatments [such as capivasertib plus abiraterone].⁴ We know that BRCA mutations, CDK12 mutations, ATM mutations, and many other tumor suppressor gene losses are associated with worse prognosis compared with patients who do not have these mutations. These patients may need to be monitored more closely, with more frequent labs and scans.

The implications are widespread. There is treatment with PARP inhibitors, which delays the resistant, symptomatic, lethal state by miles in a clinically and statistically significant fashion. But these results also affect patients’ families and children, how we monitor patients, and what other treatment options they may have. Patients may also be eligible for clinical trials because of these results.

Lastly, at least in my experience, not doing these tests may have medicolegal implications. Consider the unfortunate situation of a man with metastatic prostate cancer harboring a germline BRCA2 mutation who was not tested, and his daughter, a relatively young woman. If his children harbor that mutation, remain undiagnosed, and develop cancers down the line, that may have implications beyond the care of our patients.

It is non-negotiable and not optional anymore. Everybody has to be tested, and the way I make sure I do not miss this is to test everybody with metastatic or locally advanced disease when I see them for the first time. Every guideline now endorses this testing, and insurance payers are happy to cover it. There is no excuse anymore.

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 plus enzalutamide, be affected?

Let us say I have a patient with HRR mutation–positive, newly diagnosed metastatic prostate cancer who started treatment with talazoparib plus enzalutamide. I expect that patient to do as well as patients did in the TALAPRO-3 trial. That would be my approach: patients with HRR mutations should receive a PARP inhibitor plus an ARPI, in this case talazoparib plus enzalutamide, unless there are contraindications.

What I do after disease progression depends on the clinical state, the disease state, how the patient is feeling, and the overall disease volume. Is there neuroendocrine differentiation? What does [their prostate-specific membrane antigen (PSMA)] expression look like? Are there [androgen receptor] amplifications or [androgen receptor] mutations? What is [circulating tumor DNA (ctDNA)] testing showing us? It will depend on the overall picture of clinical and tumor characteristics.

If the patient is expressing PSMA, lutetium Lu 177 vipivotide tetraxetan [Pluvicto]–based treatment is a great option. If a patient is developing neuroendocrine-type prostate cancer, I would probably use platinum therapy. If the patient seems to have progression with liver metastases, for example, I would choose chemotherapy with docetaxel. If patients have [androgen receptor] alterations or [androgen receptor] mutations, perhaps a PROTAC [proteolysis-targeting chimera], one of the new androgen signaling inhibitors, will be approved by then. I also remain very optimistic about antibody-drug conjugates.

The bottom line is that it is an exciting time to be an oncologist and a prostate cancer doctor because we have so many more options than we had just 5 or 10 years ago.

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. Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with metastatic castration-resistant prostate cancer: final overall survival results from the randomised, placebo-controlled, phase 3 TALAPRO-2 trial. Lancet. 2026;406(10502):447-460. doi:10.1016/S0140-6736(25)00684-1
3. Hussain MH, Kocherginsky M, Pailler CJ, et al. Overall survival from the phase 2 trial of abiraterone + olaparib in first-line metastatic castration-resistant prostate cancer (mCRPC) with DNA repair defects (BRCAAway). J Clin Oncol. 2026;44(suppl 7):16. doi: 10.1200.JCO.2026.44.7_suppl.16
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