Matching mCSPC treatment to the patient, not just the trial data

The treatment landscape for metastatic castration-sensitive prostate cancer (mCSPC) has moved from androgen deprivation therapy (ADT) alone to multiple doublet and triplet regimens, each supported by phase 3 data but rarely compared head to head. With the benefit of adding an androgen receptor pathway inhibitor (ARPI) established, treatment selection increasingly turns on tolerability, drug-drug interactions (DDIs), comorbidity burden, and what patients themselves value.

These considerations anchored a series of 4 Urology Times Clinical Forum events titled "From Trial to Treatment: Applying the Latest Evidence in mCSPC Management." The forums were moderated by Kristen R. Scarpato, MD, MPH, in a virtual format; Michael S. Cookson, MD, MMHC, FACS, of the University of Oklahoma, in Tulsa, Oklahoma; Vahan Kassabian, MD, in Dunwoody, Georgia; and Mohit Narang, MD, in Chevy Chase, Maryland.

The pivotal doublet trials, including LATITUDE (NCT01715285), STAMPEDE (NCT00268476), ENZAMET (NCT02446405), ARCHES (NCT02677896), TITAN (NCT02489318), and ARANOTE (NCT04736199), largely compared an ARPI plus ADT with ADT plus placebo. Scarpato noted that without head-to-head trials, oncologic efficacy cannot be ranked across agents. Participants cited disease volume, synchronous vs metachronous presentation, cardiac history, cognitive status, genetic testing, adherence, and financial toxicity as drivers of therapy choice.

Much of the discussion centered on analyses of ARANOTE, which evaluated darolutamide (Nubeqa) plus ADT vs placebo plus ADT.¹ Health-related quality-of-life data showed longer time to pain progression and to deterioration in FACT-P total score with the combination.² Subgroup analyses presented in the deck showed consistent efficacy and comparable tolerability across age groups (younger than 65 years, 65 to 74 years, and 75 years or older) and among patients with 5 or more comorbidities or 5 or more concomitant medications.

Participants in several forums observed that most adverse events patients experience stem from ADT itself. Kassabian noted that because both ARANOTE arms received ADT, the quality-of-life difference reflected the addition of darolutamide. He said the age and comorbidity data support its use in older patients receiving multiple medications.

The phase 2 ARACOG trial (NCT04335682) randomly assigned patients with advanced prostate cancer to darolutamide or enzalutamide (Xtandi) and measured cognition with computerized CANTAB testing.³ At 24 weeks, the median change in maximally changed cognitive domain was -15.8 with darolutamide vs -36.1 with enzalutamide (P = .009), and 4 of 5 domains favored darolutamide. Participants in Tulsa and the virtual forum reported similar observations in practice, whereas a participant in Chevy Chase cautioned that cognitive change is multifactorial and that CANTAB remains a research tool.

ARASEC (NCT05059236) compared prospectively enrolled US patients receiving darolutamide plus ADT with a propensity score-matched ADT-alone cohort from CHAARTED (NCT00309985).⁴ The combination was associated with improved progression-free survival (HR, 0.29; 95% CI, 0.20-0.40) and overall survival (HR, 0.50; 95% CI, 0.30-0.82). Cookson described the design as a way to generate US-based combination data when a placebo control was no longer feasible, and Kassabian said the findings reinforced rather than changed his practice.

DDI management drew detailed discussion. Kassabian said accurate medication reconciliation begins with medical assistants at check-in and relies on the practice's pharmacy team, whereas Scarpato described leaning on specialty pharmacists and coordinating with cardiologists, most often around anticoagulants, antiplatelet agents, and statins. Chevy Chase participants described combining electronic health record alerts, pharmacist review, and artificial intelligence tools.

Kassabian emphasized that these conversations look different across communities and practice locations. He described tailoring counseling to each patient's socioeconomic and educational background, from patients who defer fully to the physician to those who arrive with extensive questions, with visits ranging from 10 to 45 minutes. He also highlighted the value of a spouse in the room, noting that a partner who has gone through menopause can relate to hot flashes and other ADT effects and help ease the transition.

That theme recurred at every forum. Narang said he asks patients to bring a family member at least twice a year, because spouses often report mood changes, fatigue, and memory lapses that patients do not volunteer. Kassabian stressed setting expectations before therapy begins and seeing patients every 3 months, noting that a decline in function can signal progression even when prostate-specific antigen levels are stable.

The forums closed with a case of a 68-year-old man with coronary artery disease, a prior myocardial infarction, diabetes, and metachronous bone metastases who wanted to stay active and independent. Participants generally favored doublet therapy, with attention to cardiac risk, DDIs, and cognition. Narang said he would choose darolutamide for this patient based on his comorbidities and goals.

Across all 4 forums, the shared message was that treatment intensification in mCSPC is no longer the open question. The task facing urologists is matching the regimen to the patient, using a team that can reconcile medications, track cognition and function, and keep caregivers involved over years of therapy.

References

1. 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

2. Morgans AK, Haresh KP, Jievaltas M, et al. Health-related quality of life (HRQoL) outcomes with darolutamide in the phase 3 ARANOTE trial. Presented at: 2025 ASCO Annual Meeting. J Clin Oncol. 2025;43(suppl_16). doi:10.1200/JCO.2025.43.16_suppl.5004

3. Morgans AK, Bobek O, Kwon DH, et al. ARACOG: cognitive effects of darolutamide versus enzalutamide in advanced prostate cancer. Presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract 5005.

4. 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