Alternate Therapy Updates

How to cite: Petrylak DP. Alternate Therapy Updates. Grand Rounds in Urology. February 2026. Accessed Oct 2026. https://grandroundsinurology.com/alternate-therapy-updates/

Summary

Daniel P. Petrylak, MD, Professor of Medicine, Yale University Cancer Center, New Haven, Connecticut, discusses novel therapeutic approaches in metastatic castration-resistant prostate cancer, emphasizing the continued central role of the androgen receptor and mechanisms of resistance to androgen receptor-targeted therapies. He notes that, despite advances in treatment, androgen receptor signaling remains active in the majority of patients, driven by mechanisms such as ligand-binding domain mutations, alternative splicing, and intracrine androgen synthesis. 

Dr. Petrylak reviews the development of proteolysis-targeting chimeras, small molecules designed to degrade disease-causing proteins via the ubiquitin-proteasome system. These agents bind to the androgen receptor and recruit E3 ubiquitin ligases, leading to targeted protein degradation. Early clinical data with ARV-110 demonstrate reductions in androgen receptor expression and prostate-specific antigen (PSA) responses, particularly in patients with ligand-binding domain mutations. Second-generation agents such as ARV-766 expand activity across additional mutations and demonstrate improved tolerability.

He discusses combination strategies involving radioligand therapy. Androgen receptor-directed agents such as enzalutamide may increase prostate-specific membrane antigen (PSMA) expression, providing a rationale for combination with lutetium-177–PSMA therapy. Early clinical data demonstrate improved progression-free survival and higher PSA response rates with combination therapy compared with androgen receptor-targeted therapy alone.

Dr. Petrylak introduces RIPTAC technology, which induces proximity between tumor-specific proteins, such as the androgen receptor, and essential cellular proteins, leading to selective cancer cell death. Early clinical studies demonstrate PSA responses across multiple molecular subtypes, including androgen receptor splice variants.

He also reviews immune-based strategies, including T-cell engagers targeting STEAP1 and PSMA. These agents redirect T cells to tumor cells and demonstrate PSA responses in heavily pretreated patients, although cytokine release syndrome remains a challenge.

Dr. Petrylak highlights that the field is moving toward personalized therapy, integrating molecular biomarkers, novel mechanisms of action, and combination strategies to improve outcomes.

The International Prostate Cancer Update (IPCU), is a multi-day, CME-accredited conference focused on new developments in prostate cancer treatment, diagnosis, and prevention. IPCU 36 featured lectures, interactive discussions, panel roundtables, debates, and case reports. This conference is led by expert physicians and is designed for urologists, medical oncologists, radiation oncologists, and other healthcare professionals involved in the diagnosis and treatment of prostate cancer.

The goal of this educational program is to equip healthcare professionals involved in the diagnosis and treatment of prostate cancer with the up-to-date clinical knowledge and tools they need to best treat their patients. The program will discuss the treatment of prostate cancer from diagnosis to treating advanced and metastatic disease. The conference aims to give physicians exposure to a comprehensive review of treating prostate cancer patients and to give them a chance to discuss the issues with peers and experts.