How to cite: Oh WK. “mCRPC: Lu-177 PSMA and Beyond.” October 25, 2025. Accessed Oct 2026. https://grandroundsinurology.com/mcrpc-lu-177-psma-and-beyond-2/
Summary
William K. Oh, MD, Professor of Medicine, Department of Oncology and Hematology, Yale School of Medicine, New Haven, Connecticut, provides a comprehensive and forward-looking overview of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy in metastatic castration-resistant prostate cancer (mCRPC), with a focus on lutetium-177 PSMA-617 (LuPSMA) and emerging next-generation agents. Dr. Oh explains why radioligand therapy has rapidly become a major pillar of advanced prostate cancer treatment and how patient selection and disease biology influence outcomes.
He begins with an epidemiologic context, highlighting rising rates of metastatic prostate cancer and increasing mortality worldwide. Dr. Oh emphasizes that prostate-specific membrane antigen positron emission tomography (PSMA PET) imaging has fundamentally reshaped disease classification, eroding the traditional distinction between non-metastatic and metastatic states and enabling molecularly targeted treatment approaches.
The biological rationale for PSMA targeting is reviewed, including its high expression in metastatic prostate cancer, upregulation with androgen deprivation therapy, and relatively limited normal tissue expression. Dr. Oh underscores that radioligand therapy is effective only in patients with PSMA-expressing disease, and he reviews the challenge of tumor heterogeneity, particularly discordant fluorodeoxyglucose (FDG)-positive and PSMA-negative lesions that predict poor response.
Key clinical trials are discussed in detail. Early Australian LuPSMA studies demonstrated high prostate-specific antigen (PSA) response rates in carefully selected patients. The TheraP trial showed superior progression-free survival and PSA response with LuPSMA compared with cabazitaxel. The VISION trial established LuPSMA as a standard of care after androgen receptor pathway inhibitor and chemotherapy, demonstrating significant improvements in radiographic progression-free survival and overall survival with acceptable toxicity.
PSMAfore demonstrated improved progression-free survival but no overall survival benefit in pre-chemotherapy mCRPC, likely influenced by crossover. SPLASH showed similar findings with an alternative lutetium compound. Phase II data from UpFrontPSMA suggest a potential benefit when radioligand therapy is initiated at the time of initial diagnosis of metastatic hormone-sensitive disease, though these findings remain exploratory.
Dr. Oh emphasizes that PSMA PET imaging is central to patient selection and that radioligand therapy will continue to expand into earlier disease states. He notes that newer isotopes, alpha emitters, and combination strategies are likely to further transform the treatment landscape.
About the 28th Annual Southwest Prostate Cancer Symposium:
Presented by Program Chairs Nelson N. Stone, MD, Richard G. Stock, MD, and William K. Oh, MD, this conference educated attendees about advances in the management of localized and advanced prostate cancer, with a focus on imaging, technology, and training in the related devices. It included a scientific session, as well as live demonstrations of surgical techniques. You can learn more about the conference here.
ABOUT THE AUTHOR
William K. Oh, MD, is the Director of Precision Medicine at the Yale Cancer Center, and a Professor of Medicine for the Division of Medical Oncology at Yale School of Medicine in New Haven, Connecticut. Dr. Oh also serves as Medical Director for the Service Line at Smilow Cancer Hospital within the Greenwich Hospital. Dr. Oh’s specialties include the management of genitourinary malignancies, including prostate, renal, bladder, and testicular cancers. Dr. Oh’s research interests include novel biomarkers and therapeutics in advanced prostate cancer.
Dr. Oh received his medical degree from New York University School of Medicine in New York, New York. He completed his internship and residency in Internal Medicine at Brigham and Women’s Hospital in Boston, Massachusetts. He then completed a fellowship in Medical Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts. Prior to joining Mount Sinai in 2009, Dr. Oh served as Clinical Director of the Lank Center for Genitourinary Oncology and directed the Gelb Center for Translational Research at the Dana-Farber Cancer Institute and Harvard Medical School in Boston. He was also the founding Chair of the Data and Safety Monitoring Committee for Phase I/II Trials at the Dana-Farber/Harvard Cancer Center.
In addition to serving as the Principal Investigator of multiple clinical trials in prostate cancer, Dr. Oh has developed large clinical databases and specimen repositories for genitourinary cancers at Harvard Medical School and the Dana-Farber Cancer Institute and at Mount Sinai, which have enrolled more than 10,000 patients with prostate, renal, and bladder cancers. Dr. Oh has authored more than 350 articles, reviews, and book chapters on topics relating to prostate, renal, bladder, and testicular cancers. He has edited three books on prostate cancer. He has served in key invited roles for the American Society of Clinical Oncology, the American Cancer Society, and the American Urological Association, including the Guidelines Committee for Advanced Prostate Cancer. In addition to reviewing for top journals such as The New England Journal of Medicine, Journal of Clinical Oncology, and Cancer, Dr. Oh co-edits “Testicular Cancer” for Up to Date and is Associate Editor of CA: A Cancer Journal for Clinicians. He is a member of the prestigious American Society for Clinical Investigation and has been repeatedly selected as a Top Doctor in New York magazine, Castle Connolly, Best Doctors, and Super Doctors over the past decade.
