How ARASEC and ARACOG are reshaping mCSPC treatment choices

A recent series of Urology Times Clinical Forum discussions, titled, "From Trial to Treatment: Applying the Latest Evidence in mCSPC Management,” convened clinicians and advanced practice teams in 4 cities. Sessions were led by Aaron Berger, MD, Chicagoland Chief Medical Officer and director of clinical research

for Associated Urological Specialists in Illinois, in Chicago; Zvi Schiffman, MD, founder and past president of Houston Metro Urology in Texas, in Houston; Sarah Arnkoff, MSN, RN, AGNP-C, an associate of Michigan Institute of Urology, in Bloomfield Hills, Michigan; and John H. Bishay, MD, co-director of the Comprehensive Prostate and Urologic Care Clinic at UroHealth Partners, in Omaha, Nebraska. Notably, the Bloomfield Hills session drew primarily advanced practice providers and oncology nurses rather than physicians, giving that discussion a distinct care-coordination lens layered onto the same clinical evidence.

Participants across all 4 forums returned repeatedly to a recent US-based phase 2 trial, ARASEC (NCT05059236), which several described as closing a long-standing evidence gap. Because ADT monotherapy is no longer considered an ethical comparator in the United States, investigators matched a prospectively enrolled darolutamide (Nubeqa)-plus-androgen deprivation therapy (ADT) cohort against a propensity-matched historical control drawn from the CHAARTED trial (NCT00309985).¹ The result, a 71% reduction in the risk of progression and a roughly 50% reduction in the risk of death compared with the matched control, was described by one Chicago participant as reinforcing rather than changing what most attendees were already doing based on the phase 3 ARANOTE trial (NCT04736199).¹^,²

Monotherapy persistence remained a recurring frustration. Schiffman polled his Houston group and noted that national estimates still place around one-third of patients with metastatic castration-sensitive prostate cancer on ADT alone, down from roughly half a few years ago, a pattern he attributed partly to outdated assumptions about tolerability in older or frailer men.² Several

participants pushed back on the idea that age alone should drive that choice, citing ARANOTE and ARASEC subgroup data showing consistent benefit regardless of age, comorbidity burden, or concomitant medication count.¹^,²

Drug-drug interactions again surfaced as the most practical differentiator among agents. Berger's Chicago group discussed a specific and often-missed interaction, darolutamide's effect on statin levels via Breast Cancer Resistance Protein inhibition, which several participants said requires proactively adjusting a patient's cholesterol medication rather than assuming the pharmacy will catch it. Multiple participants across forums noted that real-world caution around apalutamide (Erleada) and anticoagulants has eased somewhat as updated interaction data have come out, although most said darolutamide remains their default choice once a patient is on a blood thinner.

The phase 2 ARACOG (NCT04335682) cognitive data drew close attention in every session. Bishay's Omaha group discussed the crossover pattern specifically, noting that of patients who crossed over during the trial, nearly all moved from enzalutamide (Xtandi) to darolutamide and none moved the other direction, a detail several participants said was more persuasive to them than the topline cognitive scores.³ Schiffman's group in Houston, largely composed of physicians who trained before these agents existed, said the finding was consistent with what they had already suspected anecdotally about darolutamide's more limited central nervous system penetration.

Triplet therapy selection continued to hinge on disease volume, although several participants flagged that CHAARTED-era volume criteria increasingly understate true burden now that prostate-specific membrane antigen-PET imaging detects more metastatic sites than conventional imaging did when those thresholds were set. Berger noted a Decipher biomarker cut-off above which his group now favors chemotherapy intensification for high-risk disease. Across forums, participants agreed that how chemotherapy is framed to patients, as a targeted step to extend survival in high-risk disease rather than a default add-on, meaningfully affects whether patients accept it.

Cost and access were also covered in the forums. Bishay's group discussed the practical burden new Medicare fair-pricing rules place on practices that front drug costs before reimbursement, alongside enzalutamide's pending 2027 genericization and uncertainty about whether generic pricing will meaningfully lower costs. In Bloomfield Hills, Arnkoff's group of nurses and advanced practice providers detailed the granular work of navigating specialty pharmacy delays, partial-fill insurance limits, and patient assistance programs, work several said falls disproportionately on nursing staff and directly affects whether patients actually take their prescribed regimen.

Across every forum, participants converged on the same patient-reported priorities: confidence in their physician's judgment, quality time with family, and, when the disease proves fatal, the ability to die with dignity. Several nurse practitioners in Bloomfield Hills noted that patients' families, not patients themselves, often report the adverse events and cognitive changes that most affect treatment decisions. As additional agents and combinations continue to enter this space, participants generally agreed that selection will keep depending less on comparing headline hazard ratios and more on matching each patient's comorbidities, support system, and stated goals to the option most likely to keep them on 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. McKay RR, Ross AE, Preston MA, et al. Darolutamide plus androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC): ARASEC — US prospective, open-label phase 2 study with an external control arm. J Urol. 2025;213(5 suppl):e1. doi:10.1097/01.JU.0001192572.07890.f8.08

3. Bobek O, Kwon DH, Berg SA, et al. Cognitive effects of darolutamide vs enzalutamide: results of ARACOG (AFT-47), a randomized clinical trial from the Alliance for Clinical Trials in Oncology. J Clin Oncol. 2026;44(16 suppl):5005. doi:10.1200/JCO.2026.44.16_suppl.5005