Individualizing androgen pathway therapy in mCSPC

Treatment options for metastatic castration-sensitive prostate cancer (mCSPC), a disease state increasingly referred to as androgen pathway modifier-sensitive prostate cancer under the terminology adopted by Prostate Cancer Working Group 4, have expanded well beyond androgen deprivation therapy (ADT) alone. Four second-generation androgen receptor pathway inhibitors (ARPIs), abiraterone acetate (Zytiga), apalutamide (Erleada), darolutamide (Nubeqa), and enzalutamide (Xtandi), are now available, and triplet regimens that add docetaxel have moved into standard consideration for select patients. Despite hazard ratios for progression-free and overall survival that look broadly similar across the pivotal doublet trials, clinicians report considerable variability in how these agents are actually selected in daily practice, and in how aggressively combination therapy is pursued at all.

To explore that gap, Urology Times convened a series of Clinical Forum discussions built around the program "From Trial to Treatment: Applying the Latest Evidence in mCSPC Management." Sessions were led by Matthew Truesdale, MD, FACS, and Lisa Cunningham, NP-C, both of Advanced Urology Institute in Florida, in Orlando; Thomas E. Hutson, DO, PharmD, PhD, FACP, FASCO, of Texas Oncology, in Lubbock, Texas; Michael S. Cookson, MD, MMHC, FACS, of the University of Oklahoma Health Sciences Center, in Fort Worth, Texas; and Jason M. Hafron, MD, CMO, of Michigan Institute of Urology,

in Bloomfield Hills, Michigan. Across all 4 events, participants converged on a shared question: When trial-level efficacy looks similar across agents, what should actually drive selection, and when does adding chemotherapy make sense?

Despite guideline consensus that doublet therapy, ADT plus an ARPI, is standard of care for nearly all men with mCSPC, participants acknowledged that monotherapy persists in practice. Cookson cited national pharmacy audit data showing more than half of patients still receive ADT alone, a pattern he attributed largely to rural and lower-resource settings. Hutson noted that colleagues at recent urologic oncology meetings have called withholding

doublet therapy a form of malpractice given the survival and quality-of-life benefit demonstrated across LATITUDE (NCT01715285), STAMPEDE (NCT00268476), ENZAMET (NCT02446405), ARCHES (NCT02677896), TITAN (NCT02489318), and ARANOTE (NCT04736199).¹

With efficacy differences across ARPIs difficult to parse from hazard ratios alone, participants repeatedly returned to safety and tolerability as the more practical differentiator. Abiraterone requires concurrent prednisone and carries risk of mineralocorticoid excess and hepatotoxicity; enzalutamide was associated with proximal muscle weakness and mental fog attributed to greater blood-brain barrier penetration; apalutamide was linked to rash and fracture risk. Darolutamide requires twice-daily dosing but was repeatedly described as having a comparatively favorable drug-drug interaction profile, a point participants said matters given how many of these patients take anticoagulants, statins, or antiepileptics for unrelated comorbidities.

Drug-drug interactions surfaced as a recurring concern across every forum. Hafron said his group has moved away from dose-reducing apalutamide or enzalutamide in patients on apixaban or rivaroxaban, opting instead for darolutamide given its more limited interaction profile, though he noted the underlying thromboembolic risk signal remains largely theoretical. In Orlando, participants discussed the need to proactively notify cardiologists and primary care physicians when starting these agents, since statin doses often require adjustment and many outside clinicians are unfamiliar with the drugs' downstream effects, a communication gap several attendees described as a byproduct of increasingly siloed subspecialty care.

Real-world evidence added further texture to the trial data. Participants pointed to comparative real-world outcomes with darolutamide-based triplet therapy, including longer time to treatment discontinuation and next treatment relative to abiraterone-based regimens, as reassurance that pivotal-trial benefits translate outside the clinical trial setting.³ Selection for triplet therapy itself was generally volume-driven, with participants describing thresholds of roughly 3 to 4 bone lesions, or any visceral metastasis, as the point at which they would refer for chemotherapy addition, while acknowledging that roughly 1 in 5 patients discontinue docetaxel due to toxicity.⁴

Cognitive tolerability was another focal point. The ARACOG trial (NCT04335682), comparing darolutamide with enzalutamide, found a greater decline in executive function and visual memory in the enzalutamide arm, a finding attributed to darolutamide's more limited central nervous system penetration.² Several participants said this aligned with what they see clinically, particularly in older patients or those with early cognitive vulnerability, although others cautioned that isolating drug effect from the cognitive impact of ADT itself remains difficult.

Subgroup data from ARANOTE, examining outcomes by age, comorbidity burden, and concomitant medication count, showed consistent radiographic progression-free survival and safety benefit with darolutamide regardless of those factors.¹ Several participants said this evidence reassured them about intensifying therapy in older or medically complex men they might otherwise have hesitated to treat aggressively. Participants also discussed practical patient-education challenges, including a recurring pattern of patients misattributing ADT-driven hot flashes and weight gain to their newly added ARPI, a confusion that some said contributes unnecessarily to early discontinuation.

Across all 4 forums, participants returned to the same framing for treatment goals: extending life while preserving the ability to spend meaningful time with family, and, when the disease proves fatal, allowing patients to die with dignity. Several noted that patients often carry outdated associations between chemotherapy and end-of-life decline, underscoring a need for earlier, more deliberate education about docetaxel's role when used up front rather than as a last resort. As additional combinations, including PARP inhibitors and PTEN-directed agents, move earlier into the treatment algorithm, selecting among current therapies will likely depend increasingly on matching individual comorbidity, tolerability, and patient goals rather than efficacy data alone.

References

1. Saad F, Shore N, Van Poppel H, 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.

2. Morgans AK, Bobek O, Kwon, DK, 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.

3. Morgans AK, Khan N, Ghadessi M, McKay R, Chen G, George DJ. Androgen-receptor pathway inhibitors triplet therapy (ARAAT): real-world outcomes in metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2026;44(7 suppl):82.

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/NEJMoa2119115