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News|Articles|July 27, 2026

Volume, Biomarkers, and Cost Realities Guide ARPI Sequencing in Advanced Prostate Cancer

Author(s)OncLive Staff
Fact checked by: Kyle Doherty
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Key Takeaways

  • High-volume synchronous mHSPC derives OS benefit from ADT-docetaxel, whereas low-volume disease has not shown the same signal, reinforcing volume/risk stratification as first-line anchors.
  • ADT-ARPI doublets yield roughly 30%–40% OS improvements vs ADT alone; PSA ≤0.2 ng/mL by 6–7 months correlates with superior rPFS/OS and can inform expectations.
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Faculty convened at an OncLive Scientific Interchange and Workshop to discuss individualizing ARPI-based therapy in advanced prostate cancer.

When a man with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) walks into clinic today, the default is no longer androgen-deprivation therapy (ADT) alone but ADT plus an androgen-receptor pathway inhibitor (ARPI), with debate now centered on who needs a doublet, a triplet, or a biomarker-selected regimen, said Mark N. Stein, MD, of Columbia University Medical Center, during a recent OncLive® Scientific Interchange and Workshop.¹

During the workshop, Stein and a panel of academic and community oncologists worked through the disease continuum from diagnosis to castration resistance, weighing how volume, PSA kinetics, cost, and biomarkers should guide intensification.

Top Takeaways From an OncLive Workshop on Advanced Prostate Cancer

  • In CHAARTED, adding docetaxel to ADT nearly halved the risk of death in high-volume mHSPC (HR, 0.63) with no clear benefit in low-volume disease
  • All 4 approved ADT-ARPI doublets improved OS by roughly 30% to 40% versus ADT alone, and a deep PSA response (≤0.2 ng/mL) tracked with better outcomes across trials
  • Adding an ARPI to an ADT-docetaxel doublet in PEACE-1 and ARASENS cut mortality risk by 25% to 32% vs the doublet alone, at the cost of added myelosuppression

How should volume, risk, and PSA kinetics guide ARPI selection in mHSPC?

Panelists opened the session by noting that with risk stratification by high-volume disease and high-risk disease still anchor first-line decisions.² Findings from the phase 3 CHAARTED trial (NCT00309985) demonstrated that docetaxel added to ADT benefited those with synchronous (HR, 0.63; 95% CI, 0.49-0.81; P < .001) and metasynchronous (HR, 0.72; 95% CI, 0.36-1.46; P = .37) high-volume disease in terms of overall survival (OS) compared with ADT alone, however the same benefit was not observed in patients with low-volume disease.3 This pattern was reproduced in the 2023 STOPCaP meta-analysis.³,⁴

Every ADT-ARPI doublet that was discussed improved OS over ADT alone by approximately 30% to 40%, and PSA depth was a recurring theme: reaching a PSA of 0.2 ng/mL or lower by 6-7 months predicted better rPFS and OS in multiple trials.⁵⁻⁸ Choosing among them, panelists agreed, comes down less to head-to-head efficacy, which does not exist, and more to safety, interactions, and cost. "It ultimately comes down to, obviously, efficacy, but also safety and the patient that's in front of you. I don't think there's a one-size-fits-all for any particular drug," said Alexander Z. Wei, MD. Daniel Danila, MD, raised a less-discussed factor: "Medicare now caps all out-of-pocket medications to $2100 per year, both generic and brand ... I think it's a well-kept secret." Comorbidities, pill burden, and interaction profiles (darolutamide was flagged as cleanest) also shape the choice.

When does adding docetaxel or a PARP inhibitor change the calculus in mHSPC?

For higher-risk patients, the panel turned to triplet therapy. In the phase 3 PEACE-1 trial (NCT01957436), abiraterone acetate (Zytiga) added to ADT-docetaxel improved OS (HR, 0.75; 95% CI, 0.59-0.95) and progression-free survival (HR, 0.50; 95% CI, 0.34-0.71).⁹ Moreover, in the phase 3 ARASENS trial (NCT02799602), darolutamide added to ADT-docetaxel showed a similar OS benefit (HR, 0.68; 95% CI, 0.57-0.80).¹⁰ The trade-off is myelosuppression; roughly a fifth of patients discontinued treatment, mostly from docetaxel toxicity, and most panelists reserve growth factor support for dose-limiting neutropenia only.

The recently reported phase 3 ARASAFE trial (NCT05676203) of docetaxel with darolutamide/ADT found fewer grade 3-5 adverse effects (AEs) and less grade 3/4 neutropenia with the split-dose schedule, with comparable 1-year PSA responses.¹¹

Biomarker-selected triplets drew the liveliest discussion. In the phase 3 AMPLITUDE trial (NCT04497844), niraparib (Zejula) added to abiraterone-ADT in HRR-altered mHSPC improved radiographic progression-free survival (rPFS; HR, 0.63; 95% CI, 0.49-0.80; P = .0001), more so with BRCA mutations (HR, 0.52; 95% CI, 0.37-0.72; P <.0001), though OS remains immature and grade 3 or higher AEs were more frequent.¹² Panelists welcomed the option but flagged implementation gaps: germline versus somatic testing, timing sequencing before treatment starts, and a placebo-arm crossover to PARP inhibitors that muddies the OS signal. "I feel like it's like a video, like a toy that came without a user manual, like a computer that came without instructions," Stein said of applying the regimen. Wei was more skeptical of broad testing mandates: "We're doing all of this work to find perhaps like the small group of patients who may benefit ... it just seems sometimes like a misuse of resources."

How are biomarkers and new modalities reshaping care beyond mHSPC?

The panel turned to castration-resistant disease, noting non-metastatic castration-resistant prostate cancer has become vanishingly rare now that PSMA-PET detects metastases earlier than bone scan or CT does. In the phase 3 CAPItello-281 (NCT04493853) capivasertib added to abiraterone in PTEN-deficient de novo mHSPC improved rPFS overall (HR, 0.81; 95% CI, 0.66-0.98; P = .034), more with complete PTEN loss (HR, 0.68; 95% CI, 0.48-0.96), though OS was not yet different and AEs, including diarrhea and hyperglycemia, rose sharply.¹³ "CAPItello got approved without OS benefit. As long as the HR is in the right direction, which it is," said Matthew Dallos, MD; Stein added that a quality-of-life benefit, not survival, helped tip the regulatory scale.

In metastatic castration-resistant prostate cancer (mCRPC), data from the phase 3 PSMAfore trial (NCT04689828) showed switching to ¹⁷⁷Lu-PSMA-617 improved rPFS over a second ARPI after prior ARPI progression (HR, 0.49; 95% CI, 0.39-0.61), though final OS was not significantly different, attributed partly to crossover.¹⁴ The phase 3 PEACE-3 (NCT02194842) offered a contrasting signal in earlier, bone-only mCRPC: adding radium-223 to enzalutamide improved rPFS (HR, 0.71; 95% CI, 0.57-0.89) and OS (HR, 0.76; 95% CI, 0.60-0.96; P = .0096), which Stein said "has encouraged me to think about radium as a treatment in earlier disease."¹⁵ Panelists were also enthusiastic about STEAP1- and KLK2-directed T-cell engagers: xaluritamig produced confirmed PSA50 responses in about half of evaluable patients, and pasritamig produced a 42% PSA50 response rate, both in heavily pretreated mCRPC and now advancing to phase 3 testing.¹⁶,¹⁷

What unmet needs did the panel identify?

Panelists closed by naming persistent gaps: no validated way to sequence a doublet-to-triplet escalation strategy, no consensus on restaging frequency with PSMA PET versus conventional imaging, and a growing bottleneck in genetic-counseling capacity as more patients qualify for germline testing. "We have so many patients [who] are now qualifying for genetic testing, and that's a lot for one person to counsel," said Michelle Fleyshman, MD. Molecular stratifiers such as Decipher and Artera remain used inconsistently in the hormone-sensitive setting despite emerging data linking them to ARPI and triplet benefit. The panel's message: the toolkit for advanced prostate cancer is expanding faster than the testing pathways, imaging consensus, and cost navigation needed to deploy it.

References

  1. Evolving Treatments: Managing Advanced Prostate Cancer. An OncLive Scientific Interchange and Workshop. OncLive. June 16, 2026. Accessed July 23, 2026.
  2. Hussain M, Fizazi K, Shore ND, et al. Metastatic hormone-sensitive prostate cancer and combination treatment outcomes: a review. JAMA Oncol. 2024;10(6):807-820. doi:10.1001/jamaoncol.2024.0591
  3. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;36(11):1080-1087. doi:10.1200/JCO.2017.75.3657
  4. Vale CL, Fisher D, White IR, et al. What is the optimal systemic treatment of men with metastatic, hormone-naive prostate cancer? A STOPCaP systematic review and network meta-analysis. Lancet Oncol. 2023;24(7):783-797. doi:10.1016/S1470-2045(23)00230-9
  5. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer (LATITUDE). N Engl J Med. 2017;377(4):352-360. doi:10.1056/NEJMoa1704174
  6. Sweeney CJ, Martin AJ, Zielinski RR, et al. Overall survival update of enzalutamide plus androgen deprivation therapy for metastatic hormone-sensitive prostate cancer (ENZAMET). Lancet Oncol. 2023;24(4):323-334. doi:10.1016/S1470-2045(23)00063-3
  7. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488.
  8. 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. doi:10.1200/JCO-24-01798
  9. 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. doi:10.1016/S0140-6736(22)00367-1
  10. 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. doi:10.1056/NEJMoa2119115
  11. Grimm M, Fizazi K, Schmid S, et al. ARASAFE: 3-weekly versus 2-weekly docetaxel in combination with darolutamide plus androgen-deprivation therapy in metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2026;44(suppl 7):153. doi:10.1200/JCO.2026.44.7_suppl.153
  12. Attard G, Chi KN, Merseburger AS, et al. Niraparib and abiraterone acetate plus prednisone in patients with metastatic castration-sensitive prostate cancer and homologous recombination repair gene alterations (AMPLITUDE). J Clin Oncol. 2025;43(suppl 17):LBA5006) doi:10.1200/JCO.2025.43.17_suppl.LBA5006
  13. Fizazi K, et al. Capivasertib plus abiraterone versus placebo plus abiraterone in PTEN-deficient de novo metastatic hormone-sensitive prostate cancer (CAPItello-281). Ann Oncol. 2026;37(1):53-68. doi:10.1016/j.annonc.2025.10.004
  14. 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. doi:10.1016/S0140-6736(24)01653-2
  15. Gillessen S, Gallardo E, Choudhury A, et al. Final overall survival results from 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
  16. Kelly WK, Danila DC, Lin CC, et al. Xaluritamig, a STEAP1 × CD3 XmAb 2+1 immune therapy for metastatic castration-resistant prostate cancer: results from dose exploration in a first-in-human study. Cancer Discov. 2024;14(1):76-89. doi:10.1158/2159-8290.CD-23-0964
  17. Baldini C, et al. Pasritamig, a KLK2 x CD3 T-cell engager, in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2025;43(22):2515-2526. doi:10.1200/JCO-25-00678

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