Prostate Cancer Studies Show Why Personalized Treatment, Trial Diversity Matter, Dorff Says

Studies involving prostate cancer presented during the recent American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) showed the importance of paying attention to each patient’s clinical features, along with diverse trial enrollment, according to an expert from City of Hope Comprehensive Cancer Center.

Tanya B. Dorff, MD, medical oncologist and professor in City of Hope’s Department of Medical Oncology & Therapeutics Research, was invited to the opening session of ASCO GU to discuss the TALAPRO-2 and STOPCAP trials.1,2 In her remarks, Dorff said it was important “to keep patients at center as we try to apply the findings from these trials to the patient sitting in front of us."

Tanya B. Dorff, MD | Image credit: City of Hope

Health systems should support next-generation sequencing (NGS) to guide individualized treatment, she said. “We should examine our prescribing habits in the context of emerging data and continue to support clinical trials, particularly including a diversity of patients.”

ASCO GU opened in San Francisco, California, in the aftermath of an executive order to remove references to diversity, equity, and inclusion from federal health agencies and from federally sponsored scientific research.3 As the conference unfolded February 13-15, 2025, scientists were talking about the removal of an FDA draft guidance on diversity in clinical trials from the agency web site, as well as announcements of funding changes and layoffs at the National Institutes of Health.

During the February 13, 2025, oral abstract session on prostate cancer, Dorff commented on final data from TALAPRO-2 study as well as the STOPCAP study.1,2 TALAPRO-2 (NCT03395197), a phase 3 trial of talazoparib (Talzenna; Pfizer) and enzalutamide (Xtandi; Astellas/Pfizer) in men with metastatic castration-resistant prostate cancer (mCRPC) showed the combination reduced the risk of death 20.4% in patients whether or not they had homologous recombination repair (HRR) gene alterations.1 The STOPCAP Collaboration, meanwhile, culled individual patient data from 5 trial comparisons, or 2882 events involving 5472 patients, to investigate ARPI effect modifiers in patients with metastatic hormone-sensitive prostate cancer (mHSPC).2 The goal was to identify which patients benefit most from androgen receptor pathway inhibitors (ARPI) vs docetaxel plus androgen deprivation therapy (ADT) doublet.

With TALAPRO-2, investigators learned that the talazoparib and enzalutamide combination worked in both patient groups, but there were differences, and it was still important that patients receive next-generation sequencing.1 With STOPCAP, the relative benefit of ARPIs on progression-free survival (PFS) increased among younger patients, among those with higher body mass index, and among those with lower burden of metastases; these effects were also seen in overall survival.2

“My takeaway messages from TALAPRO-2 is that AR pathway inhibitors and PARP inhibitors have clearly demonstrated synergy that will extend their utility to a broader population,” Dorff said during the session. However, she said patient characteristics and molecular selection remain critical, “as this informs the likelihood of benefit, and we can use those data when counseling our patients about risk vs benefits.”

Likewise, in STOPCAP, the meta-analysis of individual patient data shows that in mHSPC, “We learned that clinical features remain the major source of treatment selection, and largely all patients benefit from intensification.”

Dorff discussed the studies in an interview with The American Journal of Managed Care® (AJMC®). This interview has been lightly edited for clarity.

AJMC: Regarding TALAPRO-2, you discussed the importance of the “synergy” between the 2 therapies, balancing this with the side effect profile. Can you elaborate on this?

Dorff: Often, when we put 2 drugs together, we get twice the toxicity, or at least more than the typical toxicity that you see with one drug or the other. But in this case, the side effect profile was essentially exactly the same, at least in TALAPRO-2, if you used talazoparib by itself vs enzalutamide by itself. So that's really great, especially because patients are on this [regimen] a long time. It means that it's tolerable. There are definitely dose reductions for anemia, but you see that regardless of whether you're using a combination approach or not.

AJMC: Is that unusual to see that?

Dorff: I think it's reassuring. We had concerns about drug-drug interaction between PARP and ARPIs, which is why talazoparib dose has to be 0.5 mg when it's together with enzalutamide, whereas the monotherapy dose would be 1 mg. In the MAGNITUDE trial (NCT03748641),4 which combined abiraterone and niraparib, there's also direct drug interaction, and we actually saw more hypertension and side effects that we associate with abiraterone than we saw on the abiraterone alone arm. So, in that case, it did seem to augment the toxicity, but we didn't see that in TALAPRO-2.

AJMC: You noted that despite findings that show benefits in groups regardless of HRR alterations, which suggest payer support for doing NGS, we still seem to have problems with getting payer coverage for NGS testing. There was a study in July 2024 in prostate and urothelial cancer that found patients who are Black or who have Medicare and Medicaid still are less likely to have access to NGS.5 Do patients need access to NGS?

Dorff: Absolutely, they do. Because we have other options in this space. PEACE-3 reported out a survival benefit with enzalutamide and radium 223 vs enzalutamide.6 It was in a similar patient population. So, if you do the NGS testing and you don't find an HR alteration, maybe you're going to choose the PEACE-3 regimen instead of the TALAPRO-2 regimen. We can’t say head-to-head what’s better in what population, but as we have choices, then we want to pick the most effective combination for the patient. So reimbursing NGS is going to really inform decision making and help the right patients get PARP inhibitor therapy, the ones who are really going to get a lot of mileage out of it.

AJMC: Based on data from STOPCAP, what new insights can be gleaned, if any, from the special challenges of trying to treat our oldest patients—those who were over 75 who were in this population with metastatic hormone-sensitive prostate cancer?

Dorff: It’s challenging, even though they had individual participant data, to really understand who these 75-year-olds were. What were their comorbidities? Did they have toxicities that made them stop taking the abiraterone? What were their [pharmacokinetics]? Maybe they weren't absorbing the drug as much as people under 65, and maybe that's why they didn't benefit. So, there are limitations to what we can learn. Even though they had individual patient data, they can say some things about outcomes, but not really drill down and explain the why.

Not every 75-year-old patient is the same. Patients who go on to trials are often called out as being the best of our patients. I really am curious about this finding. In patients over 75, I certainly have moved away from a default of [using] a lot of abiraterone in my metastatic hormone-sensitive patients because I felt like patients were having a better quality of life on that regimen than some other regimens. But now I am really thinking more about using AR antagonists. I used to worry about patients over 75 and falls and frailty, which are side effects that we see more with the AR antagonist than with abiraterone. However, these data really call that into question—whether we should avoid AR antagonists in someone over 75—because they did very well in the STOPCAP meta-analysis with those agents.

So, I think we probably need to be doing more geriatric assessments. We probably need to be paying more attention to comorbidities and really thinking about the patient in front of us, regardless of age, as far as which class of drugs might really be the best one for them.

AJMC: You mentioned the trial population in STOPCAP lacked diversity, and that this can mean that there are limitations on how much we can look at the findings and translate them into clinical practice. ASCO has placed a particular priority on improving diversity in clinical trials. Given the environment that's been going on just in the last few weeks, is there a concern among investigators about the future of clinical trial diversity?

Dorff: I think it's very hard to know in the current political climate what will happen, but we're all committed to continuing the work of improving inclusiveness and equity regardless. I think a lot of energy and effort has been invested, and that will continue to pay dividends regardless of what's happening in this moment.

We’re always concerned about it. We're always thinking about how to reduce clinical trial burden, reduce unnecessary exclusionary criteria that result in bias as to which patients end up enrolling. That's not going to go away because of whatever is happening now—that thought process and that initiative in how we write our trials, how we talk to patients, how we retain them—it’s not just about enrolling patients, but keeping them on study. And I am hopeful that we will still continue to make improvements in our diversity of our accrual.

References

1. Agrawal N, Azad A, Charles J, et al.Final overall survival with talazoparib + enzalutamide as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer in the phase 3 TALAPRO-2 trial. J Clin Oncol. 2025;43(suppl 5). doi:10.1200/JCO.2025.43.5_suppl.LBA18
2. Fisher DJ, Vale CL, Rydzewska LH, et al. Which patients with metastatic hormone-sensitive prostate cancer (mHSPC) benefit more from androgen receptor pathway inhibitors (ARPIs)? STOPCAP metaanalyses of individual participant data (IPD). J Clin Oncol. 2025;43(suppl 5):Abstract 20. doi:10.1200/JCO.2025.43.5_suppl.20
3. Grossi G. FDA quietly removes draft guidance on diversity in clinical trials following executive order on DEI. AJMC. January 31, 2025. Accessed February 21, 2025. https://www.ajmc.com/view/fda-quietly-removes-draft-guidance-on-diversity-in-clinical-trials-following-executive-order-on-dei
4. Chi KN, Rathkopf D, Smith MR, et al. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol. 2023;41(18):3339-3351. doi: 10.1200/JCO.22.01649.
5. Hage Chehade C, Jo Y, Gebrael G, et al. Trends and disparities in next-generation sequencing in metastatic prostate and urothelial cancers. JAMA Netw Open. 2024;7(6):e2423186. doi:10.1001/jamanetworkopen.2024.23186
6. Gilliseen S, Choudhury A, Saad F, et al. A randomized multicenter open label phase III trial comparing enzalutamide vs a combination of Radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): first results of EORTC-GUCG 1333/PEACE-3. Ann Oncol. 2024;35(suppl 2):Abstract LBA1. doi:10.1016/j.annonc.2024.08.2307