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Commentary|Articles|September 2, 2026

New Biomarker-Driven Regimens Prompt Debate Over Treatment Intensification in Advanced Prostate Cancer

Author(s)Onclive Team
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Key Takeaways

  • ADT plus ARPI across major trials yields PFS HRs 0.44–0.63 and OS HRs 0.61–0.81, with PSA depth strongly prognostic (eg, ARANOTE PSA <0.2 ng/mL rPFS HR 0.09).
  • Regimen choice often hinges on real-world feasibility: abiraterone’s food/steroid requirements, classwide anticoagulant interaction concerns deemed minimal, and darolutamide favored for cognition/fall-risk in older patients.
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Faculty convened at an OncLive Scientific Interchange and Workshop to weigh how new regimens should reshape sequencing in prostate cancer.

Three regulatory actions in as many months, lutetium Lu 177 vipivotide tetraxetan (Pluvicto) in hormone-sensitive disease, capivasertib (Truqap) plus abiraterone (Zytiga) in CAPItello-281, and a pending approval for talazoparib (Talzenna) plus enzalutamide (Xtandi) from TALAPRO-3, have widened the frontline armamentarium faster than the field's vocabulary has kept pace.¹ 

Faculty meeting during a recent OncLive® Scientific Interchange and Workshop noted that “androgen pathway modulator-naive” and “-sensitive” are now replacing “hormone-sensitive” terminology. With more regimens than any trial can compare head-to-head, the panel debated which patients warrant intensification and which are being over-treated.

Which factors should guide selection among ADT plus ARPI doublet regimens?

Across LATITUDE, STAMPEDE, ENZAMET, ARCHES, TITAN, and ARANOTE, ADT plus an ARPI roughly halved the risk of progression versus ADT alone (PFS HRs, 0.44-0.63), with overall survival HRs of 0.61 to 0.81.²⁻⁷ Depth of PSA response tracked with outcomes: in ARANOTE, patients reaching a PSA nadir below 0.2 ng/mL had a radiographic PFS HR of 0.09 versus those who did not. With efficacy relatively similar across the four ARPIs, faculty said differentiation comes down to practical factors. Sai Gadde, MD, cited a roughly 3,000-patient retrospective analysis showing no difference in thrombotic risk with direct oral anticoagulants across the class, calling the drug-interaction concern “a bit overblown.” Dosing logistics mattered too: Rhonda Stamey, RN, and Stephanie Corbett, NP, described patients struggling with twice-daily, food-dependent dosing and steroid pairing with abiraterone, while David Chism, MD, said cognitive and fall-risk data favoring darolutamide shape his choice in older patients.

Top Takeaways From an OncLive Workshop on Optimizing Care in Advanced Prostate Cancer

  • Selecting among ADT plus ARPI doublets increasingly hinges on comorbidities, pill burden, and dosing logistics as much as differences in trial hazard ratios.
  • Biomarker-selected regimens, niraparib plus abiraterone (AMPLITUDE), talazoparib plus enzalutamide (TALAPRO-3), and capivasertib plus abiraterone (CAPItello-281), extend rPFS benefit to HRR-altered and PTEN-deficient subsets, but carry durable toxicity, including myelodysplastic syndrome risk with PARP inhibitors.
  • Faculty were split on ATM as a predictive biomarker; TALAPRO-3's positive signal was viewed by several panelists as an outlier against the broader PARP inhibitor evidence base.

When do the data support intensifying to triplet or biomarker-selected therapy?

Triplet regimens (ADT, docetaxel, and abiraterone or darolutamide) from PEACE-1 and ARASENS improved overall survival (HRs, 0.75 and 0.68, respectively) over doublet- or docetaxel-based regimens, chiefly in high-volume disease.8,9 Newer biomarker-selected triplets extend intensification to molecularly defined subsets: AMPLITUDE (niraparib plus abiraterone) showed an rPFS HR of 0.52 in BRCA-mutated disease; TALAPRO-3 (talazoparib plus enzalutamide) showed a stronger rPFS HR of 0.48 in HRR-altered disease; and CAPItello-281 (capivasertib plus abiraterone) showed an rPFS HR of 0.81 in PTEN-deficient disease, about a quarter of the mCSPC population.¹⁰⁻¹² Paul Eber, MD, said he currently favors triplet therapy with docetaxel over years-long PARP inhibitor exposure, since chemotherapy “gets through it” in six defined cycles. Billy Ahmed, MD, said he is “still hold[ing] off” on frontline PARP inhibition outside near-complete PTEN loss, citing docetaxel-based triplet's more mature survival data. Daniel Vaena, MD, said he would favor a PARP inhibitor for BRCA-altered patients given attrition risk to later lines, but was more cautious on capivasertib, calling it “even more toxic than a PARP” for extended use. Sai Gadde, MD, cautioned that docetaxel-based triplet trials lack an ADT-plus-ARPI comparator arm, the regimen most panelists actually use, complicating cross-trial comparisons.

How is the mCRPC landscape shifting with PSMAfore and PEACE-3 data?

PSMAfore randomized ARPI-pretreated, taxane-naive mCRPC patients to 177Lu-PSMA-617 or a second ARPI, showing an rPFS HR of 0.49; final overall survival was less separated (HR, 0.91) against a comparator arm faculty considered weak given substantial crossover.¹³ PEACE-3 added radium-223 to enzalutamide in ARPI-naive mCRPC, showing rPFS (HR, 0.71) and an overall survival benefit (HR, 0.76; 24% reduction in death; P = .0096).¹⁴ Zin Myint, MD, questioned how generalizable PEACE-3 is to current practice, since most patients now receive frontline ARPI doublets rather than reaching mCRPC ARPI-naive. Paul Eber, MD, said his group is “using less and less” radium-223 as PSMA PET identifies more extensive disease and 177Lu-PSMA-617 access has expanded. Stephanie Corbett, NP, said sipuleucel-T (Provenge) remains underused despite its survival benefit, largely due to access barriers for rural patients.

What unmet needs did the panel identify?

Faculty named treatment duration as the field’s central open question. David Chism, MD, pointed to early de-escalation data on stopping ARPIs after deep response and voiced interest in combining 177Lu-PSMA-617 with immunotherapy and in optimizing its dosing, since “some could be treated for 4 doses, some should require 8.” Zin Myint, MD, said circulating tumor DNA could eventually help define how long to continue PARP inhibitors, noting that myelodysplastic syndrome risk remains poorly characterized beyond the roughly six-month windows seen in trials to date. Daniel Vaena, MD, said the pipeline, additional radioligand agents, novel AR inhibitors, and PSMA-directed radiotheranostics, is deep, but cautioned that sequencing a field moving from roughly seven active regimens to fifteen “is gonna be even harder to understand.”

References

  1. Optimizing care in advanced prostate cancer. An OncLive Scientific Interchange and Workshop. OncLive. August 27, 2026. Accessed August 31, 2026.
  2. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360.
  3. James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377(4):338-351.
  4. Sweeney CJ, Martin AJ, Stockler MR, et al. Overall survival with enzalutamide, androgen deprivation therapy, and docetaxel in metastatic, hormone-sensitive prostate cancer. Lancet Oncol. 2023;24(4):323-334.
  5. Armstrong AJ, Azad AA, Iguchi T, et al. Improving outcomes in advanced or metastatic castration-sensitive prostate cancer: ARCHES. J Clin Oncol. 2019;37(32):2974-2986.
  6. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: TITAN. N Engl J Med. 2019;381(1):13-24.
  7. Saad F, Vjaters E, Shore N, et al. Darolutamide in combination with androgen deprivation therapy in patients with metastatic hormone-sensitive prostate cancer: ARANOTE. J Clin Oncol. 2024;42(36):4271-4281.
  8. Fizazi K, Foulon S, Carles J, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer: PEACE-1. Lancet. 2022;399(10336):1695-1707.
  9. Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer: ARASENS. N Engl J Med. 2022;386(12):1132-1142.
  10. Attard G, Murphy L, Clarke NW, et al. Niraparib plus abiraterone acetate with prednisone in metastatic castration-sensitive prostate cancer with HRR gene alterations: AMPLITUDE. Presented at: 2025 ASCO Annual Meeting; Abstract LBA5006.
  11. Agarwal N, et al. Talazoparib plus enzalutamide in HRR-altered metastatic castration-sensitive prostate cancer: TALAPRO-3. Presented at: 2026 ASCO Annual Meeting; Abstract LBA5007.
  12. Fizazi K, et al. Capivasertib plus abiraterone in PTEN-deficient metastatic castration-sensitive prostate cancer: CAPItello-281. Ann Oncol. Published online October 19, 2025.
  13. Morris MJ, Castellano D, Herrmann K, et al. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer: PSMAfore. Lancet. 2024;404(10459):1227-1239.
  14. Gillessen S, et al. Enzalutamide plus radium-223 versus enzalutamide alone in metastatic castration-resistant prostate cancer: PEACE-3. Ann Oncol. 2026;37(5):736-742.

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