Availability, Tolerability, and Drug Interactions Drive ARPI Selection in mHSPC

During a Community Case Forum event in Los Angeles, California, Matthew Rettig, MD, professor of medicine and urology and medical director of the prostate cancer program at the David Geffen School of Medicine at UCLA, and participants discussed how to individualize androgen receptor pathway inhibitor (ARPI) selection for older patients with low-volume metastatic hormone-sensitive prostate cancer (mHSPC) when trial efficacy data look largely similar across agents.

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.

• Past medical history (PMH): 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; ANC (absolute neutrophil count) 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

This patient’s oligometastatic, low-volume disease and strong preference for maintaining quality of life placed the clinical conversation squarely on which ARPI to pair with androgen deprivation therapy (ADT).

Rettig reviewed results from the major phase 3 trials evaluating ADT plus ARPI doublets in mHSPC, including LATITUDE (NCT01715285), ENZAMET (NCT02446405), ARCHES (NCT02677896), TITAN (NCT02489318), and ARANOTE (NCT04736199). Across these studies, radiographic progression-free survival (rPFS) HRs clustered in a similar range, approximately 0.48 to 0.63, and overall survival HR for the studies powered to assess that end point fell in the 0.60 to 0.73 range.^1-7 Rettig pointed out that ARANOTE, the darolutamide (Nubeqa) doublet trial, was not powered for overall survival as even a secondary end point, and its rPFS HR of 0.54 (95% CI, 0.41-0.71) aligned with the field at large.⁷ Grade 3 or 4 treatment-emergent adverse events were highest in the LATITUDE abiraterone (Zytiga) population, 63%, reflecting that trial’s high-risk enrichment, whereas ARANOTE stood out with only approximately 30%.^2,7

Without direct efficacy comparisons to settle the debate, the panel’s focus shifted to tolerability, drug-drug interactions (DDIs), and patient-level factors. Rettig drew a clear structural distinction between the agents: enzalutamide (Xtandi) and apalutamide (Erleada) are potent CYP3A4 inducers that can meaningfully reduce the effectiveness of direct oral anticoagulants (DOACs) and many other drugs commonly taken by older men with comorbidities.^8.9 Darolutamide has limited central nervous system (CNS) penetration compared with the other androgen receptor inhibitors, which Rettig linked to its lower rates of falls, fractures, and CNS-related effects.

Participants reflected this calculus directly. One attendee asserted that many clinicians have experience with all of the ARPIs, and they now use darolutamide more frequently because of its adverse event profile, noting enzalutamide’s CNS penetration. Another participant agreed, noting that darolutamide is also his preferred choice, but that once-daily dosing with apalutamide, now available as a 240 mg tablet, gives it an edge in patients where simplicity matters most. Access and cost also surfaced: one attendee described a patient who had been on abiraterone for several years because he could not qualify for patient assistance programs for newer, more expensive agents.

Rettig highlighted recent subgroup analyses of ARANOTE that are particularly relevant for the kinds of patients seen in community practice. A STOPCAP Collaboration meta-analysis of individual participant data presented at the 2025 American Society of Clinical Oncology Genitourinary Cancers (ASCO GU) Symposium found that abiraterone does not improve overall survival in men older than 75, likely because cardiovascular toxicity offsets its disease control benefit in this age group.¹⁰ By contrast, enzalutamide, apalutamide, and darolutamide continued to show overall survival benefit in patients older than 75. Among the ARANOTE subgroup data presented at ASCO GU 2026, patients with 5 or more comorbidities and those receiving 5 or more concomitant medications still showed significant rPFS benefit with darolutamide, with HRs remaining below 1 and confidence intervals that did not cross 1.¹¹ The safety profile was similarly consistent across these higher-burden subgroups.

Quality-of-life data from ARANOTE reinforced these findings. Darolutamide was associated with improvement in FACT-P total scores compared with placebo, a finding Rettig contrasted with apalutamide trials, in which quality of life was preserved but not actively improved.^12,13 Rettig framed the distinction plainly: “Adverse events, to a large extent, are what the physician or investigator documents, and the quality of life is what the patient experiences.”

One attendee observed that patients with less educational resources will defer to the physician concerning the choice of ARPI rather than deciding based on trial data, and many do not have meaningful access to a choice of newer agents, making abiraterone the accessible default. Rettig acknowledged that financial toxicity and payer formularies frequently shape real-world prescribing in ways that clinical trial data cannot address.

Seventy percent of participants answered “yes” when asked whether they still use ADT alone for some patients. Rettig’s position was clear: given that adding an ARPI to ADT does not worsen and, in the case of darolutamide, actively improves quality of life, even across age and comorbidity subgroups, so he tries to always add an ARPI unless a patient cannot access a second agent.

Polling results from the live event reflected the field’s unresolved tensions:

_{DISCLOSURES: Rettig previously reported receiving speaking honoraria or consulting fees from Ambrx, Amgen, AVEO, Clovis Oncology, Roivant, Iimmune Bio, Johnson & Johnson, and Bayer; and research funding from Merck, Pfizer, Immune Bio, Novartis, and Fibrogen.}

REFERENCES

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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

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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. Shore N, Zurth C, Fricke R, et al. Evaluation of clinically relevant drug-drug interactions and population pharmacokinetics of darolutamide in patients with nonmetastatic castration-resistant prostate cancer: results of pre-specified and post hoc analyses of the Phase III ARAMIS trial. Target Oncol. 2019;14(5):527-539. doi:10.1007/s11523-019-00674-0

9. Mehra N. Invited discussant 1595MO, LBA68 and LBA69. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain.

10. 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 meta-analyses of individual participant data (IPD). J Clin Oncol. 2025;43(suppl 5):20. doi: 10.1200/JCO.2025.43.5_suppl.20

11. 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

12. Morgans AK, Haresh KP, Jievaltas M, et al. Pain and health-related quality-of-life outcomes with darolutamide in metastatic hormone-sensitive prostate cancer (ARANOTE): secondary and exploratory analyses of a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2026;27(5):614-624. doi:10.1016/S1470-2045(26)00014-8

13. Agarwal N, McQuarrie K, Bjartell A, et al. Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): a randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2019;20(11):1518-1530. doi:10.1016/S1470-2045(19)30620-5