Genomic Testing, Toxicity, and Sequencing Shape Treatment Decisions in Advanced Prostate Cancer

An expanding range of molecularly selected combinations and radioligand therapies is reshaping advanced prostate cancer management, although determining which patients require additional upfront treatment remains a central challenge, according to experts participating in an OncLive® Scientific Interchange and Workshop.¹

Throughout the workshop, urologists and medical oncologists discussed how emerging evidence should influence initial treatment selection, management after androgen receptor pathway inhibitor (ARPI) exposure, and access to investigational therapies. Benjamin A. Gartrell, MD, director of the Genitourinary Malignancy Program at Montefiore Einstein Comprehensive Cancer Center and an assistant professor of Oncology and Urology at the Albert Einstein College of Medicine both in New York, New York, and Matthew Dallos, MD, a genitourinary medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, moderated the discussion.

Additional experts that participated in the discussion were:

• Shaheer Ahmad Khan, DO, a medical oncologist at Northwell Health Cancer Institute and an assistant professor at the Donald and Barbara Zucker School of Medicine, both in Lake Success, New York,
• Kara L. Watts, MD, an associate professor of Urology, vice chair and director of urologic oncology services at Montefiore Medical Center in New York, New York
• Ilan J. Safir, MD, FACS, a urologist at Advanced Urology Centers of New York in Manhasset, New York
• Xinhua Zhu, MD, PhD, a medical oncologist and hematologist at Northwell Health Cancer Institute in Lake Success, New York

“Long-term, are they actually going to move [overall survival], or are we just intensifying therapy early?” Khan, asked. His question captured a recurring concern among experts in the discussion: how to translate earlier disease control into meaningful benefit without unnecessarily increasing treatment burden.

How should testing and patient factors guide initial treatment selection?

Genomic testing has become increasingly relevant to initial treatment decisions rather than serving primarily as preparation for subsequent lines of therapy. Gartrell described initiating androgen deprivation therapy (ADT) while awaiting somatic next-generation sequencing results before choosing an androgen receptor pathway inhibitor (ARPI) for many patients who could receive abiraterone acetate (Zytiga).¹

“I try to wait on making ARPI decisions for most patients until I get next-generation sequencing,” Gartrell said.

That approach reflects the availability of biomarker-directed intensification. The FDA approved niraparib and abiraterone acetate (Akeega) plus prednisonefor BRCA2-mutated metastatic castration-sensitive prostate cancer based on the phase 3 AMPLITUDE trial (NCT04497844). In the FDA-reported exploratory BRCA2-mutated subgroup, the radiographic progression-free survival (rPFS) hazard ratio was 0.46 (95% CI, 0.32-0.66); median rPFS was not estimable (NE; 95% CI, 41-NE) with the combination vs 26 months (95% CI, 18-28) with placebo plus abiraterone acetate and prednisone alone.²

Khan takes a different approach to timing, obtaining germline and somatic testing upfront but initiating ADT with or without an ARPI before results return.¹ He then uses genomic findings, disease burden, and prostate-specific membrane antigen (PSMA) imaging to consider additional therapy.

Dallos emphasized retaining conventional imaging for serial comparisons, even when patients undergo PSMA PET during the initial workup.

Beyond biomarkers, faculty described ARPI selection as a balance among comorbidities, cognitive effects, fatigue, drug interactions, monitoring requirements, and insurance coverage. The STOPCAP meta-analysis influenced Dallos and Gartrell to use less abiraterone in older patients, although they did not consider age alone determinative.¹˒³

“There is a wide range of 75-year-olds,”Watts, said, challenging a rigid cutoff. Dallos agreed that individual circumstances can outweigh age-based preferences.¹

Dallos emphasized confounding and differences in which patients receive each agent. His discussion underscored the limits of inferring comparative efficacy without randomized head-to-head trials.

Which patients should receive treatment beyond an ARPI doublet?

Faculty reported selective use of docetaxel triplets, generally favoring younger, fitter patients with synchronous high-volume or visceral disease. Individual estimates were approximately 30% of patients in the represented practices; these were clinician estimates rather than measured rates.

Gartrell highlighted the absence of a direct comparison with an ADT/ARPI doublet. The phase 3 ARASENS trial (NCT02799602) established an OS benefit for darolutamide (Nubeqa) plus ADT and docetaxel vs placebo plus ADT and docetaxel (HR, 0.68; 95% CI, 0.57-0.80).⁴

“The triplets with chemo have not been shown to be better than a doublet with an ARPI,” Gartrell said, identifying an unanswered comparative question rather than evidence that chemotherapy provides no additional benefit.¹

Molecularly selected combinations prompted a different benefit-risk discussion. In the phase 3 TALAPRO-3 trial (NCT04821622), talazoparib (Talzenna) plus enzalutamide (Xtandi) improved rPFS vs placebo plus enzalutamide in patients with homologous recombination repair–altered metastatic castration-sensitive disease (HR, 0.481; 95% CI, 0.357-0.647; P < .0001). Median rPFS was not reached vs 45.8 months.⁵

Enthusiasm was more restrained for capivasertib (Truqap) plus abiraterone/prednisone. In the phase 3 CAPItello-281 trial (NCT04493853), patients with PTEN-deficient disease experienced a median rPFS of 33.2 months vs 25.7 months with placebo plus abiraterone/prednisone (HR, 0.81; 95% CI, 0.66-0.98; P = .034).⁶

When should radioligand therapy enter the treatment sequence?

Earlier use of lutetium Lu 177 vipivotide tetraxetan (Pluvicto) exposed a clear division between maximizing treatment before resistance and preserving marrow reserve for later therapies.¹

Safir favored considering effective treatments earlier because some patients may never reach later lines. Dallos and Zhu expressed concern about marrow toxicity and the implications for patients who may otherwise live for years.

In resistant disease, several participants described moving radioligand therapy ahead of docetaxel, influenced by patient preferences. However, faculty scrutinized the phase 3 PSMAfore trial (NCT04689828), which compared radioligand therapy with an ARPI change in taxane-naive metastatic castration-resistant prostate cancer. Final median OS was 24.48 months vs 23.13 months, respectively (HR, 0.91; 95% CI, 0.72-1.14; P = .20).⁷

How does prior ARPI exposure affect treatment after resistance?

Upfront ARPI use has created a mismatch between contemporary practice and studies that enrolled patients without prior ARPI exposure. Gartrell noted that this limits straightforward application of some PARP inhibitor/ARPI combination data after resistance develops.¹

Similar applicability concerns arose with the phase 3 PEACE-3 trial (NCT02194842), which evaluated enzalutamide plus radium Ra 223 dichloride (Xofigo) vs enzalutamide alone. Although the study demonstrated rPFS and OS benefits, Gartrell and Zhu emphasized that its largely ARPI-naive population differs from many patients now progressing after an upfront doublet. Bone-protective therapy was another essential component of the discussion, following its mandated use during the trial to address fracture risk.¹˒⁹

What will determine adoption of emerging therapies?

Faculty expressed interest in alpha-emitting radioligands and T-cell engagers, while emphasizing that response data alone will not determine their practical value. Gartrell considered outpatient initiation and lower cytokine release syndrome burdens particularly important for emerging T-cell–redirecting treatments.¹

“We need to have drugs that are better tolerated, and I think logistics are really important,” he said.

Khan cautioned that hospitalization, monitoring, caregiver support, health literacy, and radiation-safety requirements can create unequal access. Gartrell highlighted the challenges of administering radioligand therapy to patients living in small, shared, or multigenerational homes or nursing facilities.

References

1. Optimizing care in advanced prostate cancer. An OncLive Scientific Interchange and Workshop. OncLive. September 15, 2026. Accessed November 10, 2026.
2. FDA approves niraparib and abiraterone acetate plus prednisone for BRCA2-mutated metastatic castration-sensitive prostate cancer. FDA. December 12, 2025. Accessed November 10, 2026.
   https://www.fda.gov/drugs/cancer-approvals/fda-approves-niraparib-and-abiraterone-acetate-plus-prednisone-brca2-mutated-metastatic-castration
3. Fisher DJ, et al. Which patients with metastatic hormone-sensitive prostate cancer (mHSPC) benefit more from androgen receptor pathway inhibitors (ARPIs)? STOPCAP meta-analyses of individual participant data (IPD). J Clin Oncol. 2025;43(suppl 5):20. doi:10.1200/JCO.2025.43.5_suppl.20.
4. Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115.
5. Agarwal N, 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. J Clin Oncol. 2026;44(suppl 17):LBA5007. doi:10.1200/JCO.2026.44.17_suppl.LBA5007.
   https://ascopubs.org/doi/10.1200/JCO.2026.44.17_suppl.LBA5007
6. Fizazi K, Clarke NW, De Santis M, et al. Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study. Ann Oncol. Published online October 19, 2025. doi:10.1016/j.annonc.2025.10.004.
7. FDA approves lutetium Lu 177 vipivotide tetraxetan with androgen receptor pathway inhibitor therapy. FDA. July 31, 2026. Accessed November 10, 2026.
   https://www.fda.gov/drugs/cancer-approvals/fda-approves-lutetium-lu-177-vipivotide-tetraxetan-androgen-receptor-pathway-inhibitor-therapy
8. Fizazi K, Chi KN, Shore ND, et al. Final overall survival and safety analyses of the phase III PSMAfore trial of [177Lu]Lu-PSMA-617 versus change of androgen receptor pathway inhibitor in taxane-naive patients with metastatic castration-resistant prostate cancer. Ann Oncol. 2025;36(11):1319-1330. doi:10.1016/j.annonc.2025.07.003.
9. Gillessen S, Gallardo E, Choudhury A, et al. Final overall survival results from the EORTC 1333/PEACE-3 trial of enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer. Ann Oncol. 2026;37(5):736-742. doi:10.1016/j.annonc.2026.02.009.