How to cite: Crawford ED. “Navigating the Management of mCSPC from Mono to Quadruple Therapies.” Grand Rounds in Urology. November 2025. Accessed Jan 2026. https://grandroundsinurology.com/navigating-the-management-of-mcspc-from-mono-to-quadruple-therapies/
Summary
E. David Crawford, MD, of the University of California, San Diego, La Jolla, California, reviews the historical development and current therapeutic framework for metastatic castrate-sensitive prostate cancer. He traces the origins of hormonal manipulation from early orchiectomy and estrogen therapy to the Nobel Prize–winning discoveries of Huggins and Hodges, the advent of luteinizing hormone–releasing hormone (LHRH) agonists, and subsequent generations of antiandrogens.
Dr. Crawford highlights key milestones that transformed the field, including the first antiandrogen monotherapy trials, the identification of adrenal and intratumoral androgen production, and the seminal 1989 Southwest Oncology Group intergroup study, which demonstrated a 26 percent survival improvement with combined androgen blockade. He notes that these findings established the foundation for multi-agent therapy.
Modern management has evolved through the use of doublet and triplet combinations, incorporating LHRH agonists or antagonists, docetaxel chemotherapy, and next-generation androgen-receptor inhibitors such as enzalutamide, apalutamide, or darolutamide. Dr. Crawford explains that triplet therapy data, including the ARASENS and ARASENS-like studies, show improved survival without additive toxicity beyond the docetaxel-based backbone. He stresses that direct statistical comparisons across doublet and triplet trials are inappropriate due to the differing designs, agents, and patient populations.
Dr. Crawford argues that comprehensive combination therapy now defines the standard for fit patients with mCSPC, reflecting decades of incremental progress from surgical castration to layered hormonal and cytotoxic approaches. He also emphasizes ongoing discussion of potential “quadruple” strategies that integrate novel agents while maintaining tolerability.
ABOUT THE AUTHOR
Researcher-physician E. David Crawford, MD, Jack A. Vickers Director of Prostate Research and Professor of Urology at the University of California, San Diego, has devoted his career in medicine to educating the public about men's health issues and finding effective techniques and procedures to address prostate cancer, the most common malignancy affecting men in the United States.
