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Evolving Treatment Strategies in Metastatic Castration-Resistant Prostate Cancer

Clinical Thought

In this commentary, expert faculty reviews the evolving treatment landscape for metastatic castration-resistant prostate cancer (mCRPC), with emphasis on biomarker-driven therapy, combination strategies, radiopharmaceuticals, and emerging approaches for overcoming resistance. The faculty also examines real-world gaps in germline and somatic testing; phase III data supporting PARP inhibitor/ARPI combinations, PSMA-targeted radioligand therapy, and radium-223 plus enzalutamide; and the role of PTEN-directed AKT inhibition in advanced prostate cancer. Investigational approaches targeting EZH2, CYP11A1, mutant or persistent androgen receptor signaling, and tumor-associated cell-surface targets are also highlighted. Together, these data underscore the importance of early comprehensive biomarker testing, appropriate sequencing of established therapies, toxicity and supportive care considerations, and clinical trial participation when standard options are limited.

Released: September 01, 2026

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Provided by Clinical Care Options, LLC dba Decera Clinical Education

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Supporters

Supported by an educational grant from Bristol Myers Squibb.

Bristol Myers Squibb

Target Audience

This activity is intended for oncologists, urologists, and other healthcare professionals caring for patients with prostate cancer.

Learning Objectives

Upon completion of this activity, participants should be able to:

  • Describe the biologic rationale for novel mechanistic targets driving resistance in mCRPC, including androgen receptor (AR) protein degradation

  • Interpret key clinical trial data for investigational agents targeting EZH2, CYP11A1, AR degradation, PI3K-AKT-mTOR, and immune pathways

  • Apply clinical evidence to patient-specific decision-making and trial referral in advanced prostate cancer

Financial Disclosures

Primary Author

Neal D. Shore, MD, FACS: consultant/advisor/speaker: Accord, Alessa, Amgen, Asieris, Astellas, AstraZeneca, Aura, Bayer, BioProtect, Bristol Myers Squibb, CG Oncology, Clarity, Dendreon, Ferring, Fize Medical, Glytherix, Immunitybio, Invitae, Janssen, Lantheus, Lilly, Mdxhealth, Merck, Minomic, Myriad, Novartis, Nusano, Pfizer, Photocure, PlatformQ, Promaxo, Protara, Sumitomo, Telix, Tolmar, Tutelix, UroGen.

Additional Disclosures

Generative artificial intelligence (AI) tools were used for data analysis or summarization influencing content. All AI-assisted content underwent human review, editing, and validation by qualified faculty and accredited education staff to ensure scientific accuracy, balance, and compliance with the ACCME Standards for Integrity and Independence in Accredited Continuing Education.