Doublet or triplet? Urologists weighs in on mCSPC options

Metastatic castration-sensitive prostate cancer (mCSPC) is no longer managed with a single standard regimen. Over the past decade, androgen deprivation therapy (ADT) paired with an androgen receptor pathway inhibitor (ARPI), and in select patients a triplet that adds docetaxel, has replaced ADT alone as the evidence-based approach. With 4ARPIs now available in the doublet setting and comparably strong trial data behind each, clinicians are left weighing efficacy, safety, cognitive effects, drug interactions, and patient priorities without head-to-head data to guide the choice.

That tension framed a recent series of 4 Urology Times Clinical Forum events held across the country, each built around the program “From Trial to Treatment: Applying the Latest Evidence in mCSPC Management” and led by a different moderator: David S. Yee, MD, MPH, in Roseville, California; Gregory Larsen, MD, in Des Moines, Iowa; Christopher M. Pieczonka, MD, in a virtual forum; and Michael S. Cookson, MD, MMHC, FACS, in Tulsa, Oklahoma. Across the 4 discussions, participants worked through how to individualize systemic therapy for newly diagnosed mCSPC in the absence of comparative trials among the available agents.

Each forum began with the pivotal doublet data. Trials including LATITUDE (NCT01715285), STAMPEDE (NCT00268476), ENZAMET (NCT02446405), ARCHES (NCT02677896), TITAN (NCT02489318), and ARANOTE (NCT04736199) have each shown a survival and progression-free survival benefit for ADT plus an ARPI, whether abiraterone acetate (Zytiga), enzalutamide (Xtandi), apalutamide (Erleada), or darolutamide (Nubeqa), over

ADT alone.¹ Yee described the result as “an embarrassment of riches,” noting that differences in dosing, pill burden, and adverse event (AE) profiles, more than efficacy, often drive selection in practice. Participants at multiple forums flagged drug-drug interactions as a practical differentiator, particularly for patients on anticoagulation, where darolutamide and abiraterone were repeatedly described as easier to manage than apalutamide or enzalutamide.

Quality of life data featured prominently. Yee referenced survey findings showing that efficacy rarely ranks as patients’ top priority, and that maintaining function and time with family often matters more. That context grounded discussion of ARANOTE health-related quality of life outcomes, which showed a statistically significant delay in pain progression and in deterioration of FACT-P scores with darolutamide plus ADT compared with placebo plus ADT.¹

Subgroup analyses presented at the forums extended this benefit across age groups, including patients older than 75 years, and across patients with 5 or more comorbidities or concomitant medications, without a corresponding rise in serious AEs.¹

Cognitive safety drew sustained attention, particularly at the Yee and Pieczonka forums. The ARACOG study (NCT04335682), a randomized phase 2 trial comparing objectively measured cognitive change between darolutamide and enzalutamide, found a significantly greater decline in cognitive testing scores with enzalutamide across four of five domains assessed at 24 weeks.² Pieczonka relayed a hypothesis raised in his forum that differences in blood-brain barrier penetration between the two agents may help explain the divergence, while acknowledging that formal cognitive screening is not yet part of routine practice for most participants. Real-world data from the ARASEC study (NCT05059236), an open-label comparison of darolutamide plus ADT against a historical ADT-only cohort from CHAARTED, reinforced the doublet’s activity outside the trial setting, with participants at the Pieczonka forum noting a favorable radiographic progression-free survival signal alongside a safety profile consistent with prior studies.³

Triplet therapy generated the most varied practice patterns. Data from ENZAMET, PEACE-1 (NCT01957436), and ARASENS (NCT02799602) support adding docetaxel to ADT and an ARPI in select patients, with the clearest survival benefit seen in high-volume disease.⁴ At the Larsen forum, participants described reserving the triplet for younger patients with good performance status and high-volume metastases, typically initiating ADT first to confirm tolerability before involving medical oncology for chemotherapy. Cost and insurance-driven steering were raised as recurring, practical constraints on agent selection across the forums, alongside the logistics of coordinating anticoagulation and comorbidity management with primary care and cardiology.

Each forum closed with a shared patient case, a 68-year-old former teacher with cardiovascular comorbidities and biochemically recurrent, now metastatic, prostate cancer who prioritized independence and time with his grandchildren. The exercise consistently surfaced the same tension participants had been working through all evening: efficacy differences among the ARPIs are narrow, but differences in interaction risk, cognitive effect, and administration burden are not, and matching those factors to an individual patient’s comorbidities and goals is where the clinical judgment actually happens.

Taken together, the 4 forums reflected a field with more effective options than it has practical ways to choose among them. As subgroup and real-world data continue to accumulate for each ARPI, the moderators and their participants agreed that individualized decision-making, grounded in comorbidities, drug interactions, cognitive risk, and what patients themselves value, will remain central to mCSPC management.

REFERENCES

1. Saad F, Vjaters E, Shore N, et al. Darolutamide plus androgen deprivation therapy in metastatic hormone-sensitive prostate cancer (ARANOTE). J Clin Oncol. 2024;42(36):4271-4281. doi:10.1200/JCO-24-01798.

2. Morgans AK, Bobek O, Kwon DH, et al. ARACOG: cognitive effects of darolutamide versus enzalutamide in advanced prostate cancer. Presented at: American Society of Clinical Oncology Annual Meeting; 2026. Abstract 5005.

3. McKay R, Ross AE, Preston MA, et al. ARASEC: A novel pragmatic trial design comparing darolutamide plus ADT versus ADT in US patients with metastatic hormone-sensitive prostate cancer using propensity score matching with an external phase 3 trial control arm. J Urol. 2025;213(5S). doi:10.1097/01.JU.0001109788.ARASEC

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/NEJMoa211911