Recent findings from a comprehensive analysis of androgen receptor pathway inhibitors (ARPIs) suggest that these agents demonstrate similar efficacy in treating metastatic hormone-sensitive prostate cancer (mHSPC), regardless of disease volume or timing of metastases development. This insight shifts the focus of treatment selection toward patient-specific factors rather than expected differences in cancer outcomes.
"If you really only take away one point [from the study, it] is that on the macro level, all ARPIs performed similarly [in terms of efficacy]," stated Dr. Alan H. Bryce, chief clinical officer and professor in the Department of Molecular Medicine at the Translational Genomics Research Institute and oncologist at City of Hope Cancer Center Phoenix. "The message for the [oncologist is that they] need to think about comorbidities and patient-specific factors when choosing amongst the various ARPIs."
Comparative Efficacy Across ARPIs
Using the living interactive evidence synthesis framework, investigators conducted a systematic review of ARPI efficacy in mHSPC patients, incorporating data from phase 3 randomized controlled trials evaluating treatment intensification with abiraterone acetate (Zytiga), apalutamide (Erleada), darolutamide (Nubeqa), and enzalutamide (Xtandi).
Findings presented at the 2025 Genitourinary Cancers Symposium indicated that mixed treatment comparisons showed no significant differences in radiographic progression-free survival based on disease volume and timing of metastases development. Additionally, the addition of darolutamide to androgen deprivation therapy (ADT) did not confer superiority over other ARPIs.
While cross-trial comparisons have limitations, evidence suggests that enzalutamide may offer a slight benefit over abiraterone acetate plus prednisone for patients with low-volume or de novo metastatic disease. However, Dr. Bryce cautions that this difference is marginal.
Practical Considerations for ARPI Selection
Dr. Ganesh Raj highlighted important practical considerations for each ARPI when treating mHSPC patients:
For abiraterone plus prednisone, clinicians should avoid combination with radium-223 (Xofigo) and monitor for mineralocorticoid excess, which can be managed by titrating prednisone.
Apalutamide and enzalutamide both cross the blood-brain barrier, raising concerns about seizure risk in susceptible patients. Enzalutamide in particular is associated with more profound fatigue compared to other ARPIs.
Darolutamide has a newer warning for ischemic heart disease. Despite not crossing the blood-brain barrier, patients with prior seizure history were excluded from clinical trials, leaving uncertainty about its seizure risk profile.
Drug-Drug Interactions: A Key Differentiator
Data presented at the 2024 European Society for Medical Oncology Annual Congress revealed significant differences in drug-drug interaction potential among ARPIs:
"Abiraterone and prednisone has the lowest drug-drug interaction profile," Dr. Raj explained. "Enzalutamide, apalutamide, and darolutamide have some degree of drug-drug interactions that you have to worry about."
When tested against 980 commonly used medications, enzalutamide and apalutamide showed the highest number of relevant or severe interactions, while darolutamide and abiraterone demonstrated significantly fewer problematic interactions.
Trial Outcomes Across Disease Volume
Comparing trial results across different ARPIs in combination with ADT reveals some variations in hazard ratios (HRs) based on disease volume:
For high-volume disease, the overall survival HR for LATITUDE (abiraterone plus ADT) was 0.62, while the more recent ARANOTE (darolutamide) showed an HR of 0.8.
For low-volume disease, HRs ranged from 0.5 (ENZAMET and TITAN trials using enzalutamide and apalutamide, respectively) to 0.9 (ARANOTE).
"There were different numbers, but overall, the HRs for all of these metastatic combinations favor using either enzalutamide or apalutamide, and these two are virtually identical," noted Dr. Raj. "For the ENZAMET and the TITAN studies, these numbers virtually overlap, and the graphs virtually overlap perfectly."
Clinical Implications
Given the comparable efficacy between ARPIs, selection should be driven by drug- and patient-specific factors, including toxicity profiles, potential drug interactions, cost, and accessibility.
The most meaningful clinical decision-making will center on choosing the agent with the most favorable adverse effect profile for the individual patient rather than expecting substantial differences in prostate cancer outcomes.
This evidence-based approach allows clinicians to personalize treatment selection based on patient characteristics, comorbidities, and concomitant medications, potentially improving tolerability and adherence while maintaining efficacy in managing mHSPC.
