Oncologists Weigh Patient Goals, AEs, and Cost in Treating Low-Volume mHSPC

For metastatic hormone-sensitive prostate cancer (mHSPC), the addition of an androgen receptor pathway inhibitor (ARPI) to androgen deprivation therapy (ADT) is standard, but experienced oncologists have their own preferences and rationales for which ARPI to use.

In a virtual Community Case Forum event in partnership with the Rocky Mountain Oncology Society, Manojkumar Bupathi, MD, MS, a medical oncologist at Rocky Mountain Cancer Centers in Greenwood Village, Colorado, and executive co-chair of the Genitourinary Cancer Research Executive Committee at Sarah Cannon Research Institute, walked participants through the pivotal ARPI doublet data and moderated discussion of a case built around an active, otherwise healthy patient with low-volume oligometastatic disease.

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CASE SUMMARY

A 74-year-old man with an active lifestyle and no family history of prostate cancer presented with mild urinary hesitancy and nocturia. He denied significant fatigue and weight loss. He walks 2 to 3 miles daily and participates in weekly golf. He lives with his spouse and values maintaining his physical activity.

• Medical history: diabetes, hypertension, and hyperlipidemia; all well controlled with medication
• Transrectal ultrasound (TRUS) and biopsy reveal adenocarcinoma of the prostate gland; Gleason score 7 [3+4] with disease in 3/12 cores
• Notable labs: prostate-specific antigen (PSA) 12 ng/mL; hemoglobin 12.8 g/dL; absolute neutrophil count (ANC) 2.4
• PSMA-PET imaging shows no evidence of metastatic disease.
• Diagnosis: localized prostate cancer
• He undergoes robotic radical prostatectomy (RP); subsequent PSA (less than 0.1 ng/mL).
• Postoperatively, patient recovers well but reports mild stress urinary incontinence, requiring 1 pad per day, and erectile dysfunction, which he finds distressing but manageable.
• Imaging: post-RP CT scan and bone scintigraphy show no residual disease
• Patient gradually returns to baseline activity, but he notes some ongoing impact on quality of life.

Eighteen months later: PSA 6.2 ng/mL; hemoglobin 12.5 g/dL; ANC 2.2

• Imaging: PSMA-PET imaging shows 1 avid pelvic lymph node and a single metastatic lesion in the left iliac bone
• Patient remains symptomatic with an ECOG performance status 0, but expresses concerns about preserving independence, avoiding treatment-related fatigue, and avoiding frequent clinic visits.
• Diagnosis: metastatic prostate cancer
• Germline and somatic genetic testing are negative
• He is referred to a medical oncologist.
• Therapeutic options were reviewed with the patient as part of shared decision-making.
• He prefers oral therapy and wishes to avoid chemotherapy, prioritizing minimizing adverse effects and maintaining quality of life.

EVENT RECAP

When Bupathi polled the group on which regimen they would recommend, the vote split almost evenly across all 4 options, with ADT plus darolutamide (Nubeqa) and ADT plus abiraterone (Zytiga) plus prednisone drawing the largest shares. In the 5 pivotal trials establishing ADT-ARPI doublets in mHSPC, LATITUDE (NCT01715285, abiraterone), ENZAMET (NCT02446405, enzalutamide [Xtandi]), ARCHES (NCT02677896, enzalutamide), TITAN (NCT02489318, apalutamide [Erleada]), and ARANOTE (NCT04736199, darolutamide), radiographic progression-free survival hazard ratios clustered between roughly 0.36 and 0.63, and overall survival hazard ratios fell between about 0.61 and 0.81, with overlapping confidence intervals across every drug.^1-7

One participant, explaining a vote for ADT plus darolutamide, said simply that it was “the least toxic option, with less central nervous system [CNS] toxicity, and if he wants to preserve everything he has, that's the right answer.” Bupathi said he would have chosen neither doublet, favoring instead stereotactic radiation to the 2 small metastatic sites with either observation or ARPI monotherapy alone. “There's no wrong answer at all,” he told the group. “It's technically metastatic disease, and you could use any one of these options as a treatment option, and it would be just as good.”

Without direct comparisons for efficacy, the discussion pivoted almost entirely to tolerability, drug-drug interactions, and cost. Bupathi described avoiding enzalutamide as first-line therapy in his own practice: “I personally don't use [enzalutamide] at all upfront. I think the fatigue is way too high clinically, and the cognitive effects are much more pronounced.” Several participants echoed that experience, citing fatigue, gait instability and falls, and delayed-onset diarrhea.

Anticoagulation was discussed as a recurring issue, since apalutamide carries substantial interaction potential with agents like warfarin, though participants noted apixaban remains usable in combination. Cost was brought up repeatedly: one participant noted that even with a $2000 annual out-of-pocket cap under Medicare, older patients remain apprehensive about the expense and sometimes mistrust that the benefit will last, whereas abiraterone's generic availability made it the default for some practices with cost-sensitive populations. Subgroup analyses of ARANOTE, examining outcomes by age, comorbidity burden, and concomitant medication count, showed the darolutamide benefit held regardless of those factors,⁸ a reassurance point Bupathi raised directly with the group when discussing patients who are older or have medically complex situations.

Adding docetaxel to an ADT-ARPI doublet was discussed mainly as a contrast rather than an option for this particular patient, whose low-volume, asymptomatic disease and preference to avoid chemotherapy make him a poor candidate. The pivotal PEACE-1 (NCT01957436) and ARASENS (NCT02799602) trials established a survival benefit for triplet regimens, and real-world data presented at this year's ASCO Genitourinary Cancers Symposium meeting suggested darolutamide-based triplets outperformed abiraterone-based triplets on time to PSA normalization and time to next treatment,⁹ though participants were candid that this comparison likely reflects healthier patient selection rather than a true drug effect. One participant flagged an emerging, still-investigational wrinkle: early data on capivasertib (Truqap), an AKT inhibitor, paired with an ARPI and ADT in PTEN-deficient mHSPC (CAPItello-281), generated interest. In June, after the event took place, the FDA approved capivasertib plus abiraterone and prednisone in PTEN-deficient mHSPC.¹⁰

For this patient, the tolerability calculus extends even further than most guidelines address. Bupathi noted that most of the fatigue, hot flashes, and bone loss patients attribute to their ARPI actually originates from the ADT backbone, not the ARPI itself, and that ARPI monotherapy without ADT, while not formally established practice, has worked in select cases, including one participant's patients with severe mood disorders or suicidal ideation who could not tolerate ongoing testosterone suppression. Bupathi also described giving patients who receive long-term ARPI periodic treatment holidays, holding the drug for several months once disease is controlled and reintroducing it only if PSA begins to rise, an approach several participants said they use to keep patients “in the game” for the years of sequential therapy still ahead of them without exhausting their tolerance for treatment early.

For this patient, the oncologists evaluated matching the regimen to a patient who has an active lifestyle: whichever ARPI keeps him furthest from fatigue, falls, and frequent laboratory tests would be ideal.

Polling results from the live event reflected the field's near-even split.

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DISCLOSURES: Bupathi previously reported consulting/advisory role from AstraZeneca, Bristol-Myers Squibb, and Exelixis; honorarium from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Exelixis; Janssen, Myovant Sciences, and Pfizer, and speakers’ Bureau for Astellas Pharma; AstraZeneca, Bristol-Myers Squibb, Exelixis, Janssen Oncology, and Pfizer.

REFERENCES

1. 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. doi:10.1056/NEJMoa1704174

2. Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019;20(5):686-700. doi:10.1016/S1470-2045(19)30082-8

3. Sweeney CJ, Martin AJ, Stockler MR, et al. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(4):323-334. doi:10.1016/S1470-2045(23)00063-3

4. Zhang A, Zhang AY, Davis ID, Thomas H, et al; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). 8-year outcomes of enzalutamide (ENZA) versus a non-steroidal anti-androgen (NSAA) for metastatic, hormone-sensitive prostate cancer (ENZAMET; ANZUP 1304). J Clin Oncol. 2025;43(suppl_16):5090. doi:10.1200/JCO.2025.43.16_suppl.5090

5. Armstrong AJ, Azad AA, Iguchi T, et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2022;40(15):1616-1622. doi:10.1200/JCO.22.00193

6. 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

7. Saad F, Vjaters E, Shore N, et al. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the Phase III ARANOTE trial. J Clin Oncol. 2024;42(36):4271-4281. doi:10.1200/JCO-24-01798

8. Saad F, Haresh KP, Vjaters E, et al. Efficacy and safety of darolutamide and ADT in patient subgroups by baseline comorbidities and concomitant medications: ARANOTE post hoc analyses. J Clin Oncol. 2026;44(suppl 7):178. doi:10.1200/JCO.2026.44.7_suppl.178

9. Bilen MA, Brown GA, Singhal M, et al. Real-world comparison of prostate-specific antigen (PSA) response in metastatic castration-sensitive prostate cancer (mCSPC) patients treated with apalutamide (APA) without docetaxel vs darolutamide (DARO) without docetaxel. J Clin Oncol. 2026;44(suppl 7):106. doi:10.1200/JCO.2026.44.7_suppl.106

10. FDA approves capivasertib with abiraterone and prednisone for PTEN-deficient androgen pathway modulation-naïve or -sensitive prostate cancer. News release. FDA. June 12, 2026. Accessed August 19, 2026. https://tinyurl.com/3speetya