At the 2025 American Urological Association (AUA) conference, new developments in metastatic castration-resistant prostate cancer (mCRPC) took center stage, particularly in the evolving field of radioligand therapy (RLT). Dr. Scott Tagawa, Director of the Genitourinary Research Program at Weill Cornell Medicine in New York and a leading authority in RLT, shared insights from his work that extend beyond the currently approved lutetium-based PSMA therapies.

Dr. Tagawa explained the rationale behind targeting prostate-specific membrane antigen (PSMA), a cell surface protein expressed on most—but not all—prostate cancer cells. Early efforts used antibodies that targeted the internal portion of PSMA, which were less effective for treating viable cancer cells. This led to the development of antibodies like J591 (now known as rosopatamab), designed to bind the external domain of PSMA.

A key distinction in Dr. Tagawa’s research is his use of antibodies rather than the small molecules typically used in PSMA-targeted RLTs. Antibodies are significantly larger, resulting in longer circulation times—days instead of hours—which may offer extended tumor-targeting potential, particularly in tumors with lower PSMA expression. However, this also means antibodies are cleared by the liver, not the kidneys, and interact differently with normal tissues such as bone marrow. Importantly, their size prevents them from entering tissues with low PSMA expression, such as salivary glands and kidneys—common sites of toxicity in small-molecule PSMA RLTs.

Since 2017, Dr. Tagawa has led five clinical trials exploring J591 linked to actinium-225, an alpha-emitting radioisotope. Compared to the beta-emitting lutetium, actinium delivers higher linear energy transfer over a shorter range, increasing its potency while potentially minimizing off-target effects. At AUA 2025, Dr. Tagawa presented analyses from two of these trials.

A central theme was the comparison between single-agent actinium-based PSMA therapy and various combination strategies. Drawing on principles from medical oncology, Dr. Tagawa emphasized that, when safe, combination therapy may provide deeper, more durable responses and greater potential for cure by tackling tumor heterogeneity and resistance.

The combinations under investigation included:

• Two different PSMA-targeting agents (J591 antibody + a small molecule)
• An alpha emitter (actinium) + a beta emitter
• Actinium-225 + an androgen receptor (AR) inhibitor + pembrolizumab, an immune checkpoint inhibitor

While PSA response rates were only slightly better with combinations—and not statistically significant after multivariate analysis—progression-free survival (PFS) and especially overall survival (OS) were significantly improved. Although the studies were limited to early-phase (I/II) trials, the results are considered hypothesis-generating and support the idea that well-designed combinations could enhance long-term outcomes.

In terms of safety, the overall rate of adverse events was comparable between monotherapy and combinations. However, combinations did show a slightly higher rate of high-grade toxicities, which was expected given the use of multiple agents.

Long-term safety remains a priority. Dr. Tagawa noted that analyses are ongoing for persistent side effects such as prolonged cytopenias and potential renal toxicity. He shared that his team has more than a decade of follow-up on patients treated with lutetium PSMA. While serious long-term complications like MDS (myelodysplastic syndrome) and AML (acute myeloid leukemia) have been reported with other therapies, establishing causality is difficult without randomized long-term data. Nonetheless, Dr. Tagawa noted that if combination therapies extend survival, then the emergence of long-term toxicities becomes a “fortunate problem”—a challenge that arises only because patients are living longer.

Looking ahead, Dr. Tagawa envisions a future where combinations of radioligand therapies become standard practice. He pointed to studies combining approved agents—such as radium-223 (an alpha emitter) with PSMA-targeting beta emitters—as examples of practical, immediately actionable combinations. He also suggested that combining therapies might allow for dose reduction of individual agents, improving safety while maintaining or enhancing efficacy, though more data is needed to support this approach.

Source.