The outcomes of patients with advanced prostate cancer have improved since the US Food and Drug Administration (FDA) approvals of radiopharmaceutical therapies, and novel radiopharmaceuticals and targets are under investigation. Studies presented at the 2025 ASCO Annual Meeting focused on radiopharmaceutical therapies for patients with advanced prostate cancer.

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Following these presentations, featured expert Jeremie Calais, MD, PhD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Calais on these findings are presented here.

Radiopharmaceuticals are now expanding way beyond just prostate cancer. This dual approach of using an imaging and a therapeutic agent against the same target can potentially be replicated in many other diseases, similar to immunotherapy. I think that it is the next wave of treatment.

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In prostate cancer, radiopharmaceutical targets other than prostate-specific membrane antigen (PSMA) are also under exploration, including hK2, PSCA, DLL3, CD46, TROP2, and STEAP1. PSMA is great because it is highly overexpressed by the majority of prostate cancer cells. However, there are still many prostate cancer cells that do not express PSMA, and those that do may ultimately lose expression, so other targets are also needed. Potentially 10 to 20 years from now, we may have multiple molecular targets available for radiopharmaceutical therapy and imaging. In the future, we may be able to see, in a patient-specific way, which targets are sufficiently expressed or are not in line with available therapeutic agents, and patients can then get treatments based on their individual target expression profile.

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In addition, I think that combination therapies are really the next big thing, too. In patients whose prostate cancer has bone metastases, bone remodeling can be targeted with radium-223 therapy. There is the potential to have dual-targeting effects, such as with the combinations of enzalutamide (target: AR) and ¹⁷⁷Lu-PSMA (target: PSMA) or radium-223 (target: bone metastases).

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The combination of radium-223 with enzalutamide was evaluated in the PEACE-3 trial and showed positive results in patients with metastatic castration-resistant prostate cancer. Further, the RALU trial showed that it is safe to use ¹⁷⁷Lu-PSMA after radium-223 and vice versa, so sequencing radium-223 before or after ¹⁷⁷Lu-PSMA can be considered. And the AlphaBet study, which is being conducted by investigators from Australia, is combining ¹⁷⁷Lu-PSMA-I&T with radium-223 to try to improve the antitumor efficacy in bone lesions.

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Researchers are also evaluating the combinations of chemotherapy with ¹⁷⁷Lu-PSMA-617, PARP inhibitors with ¹⁷⁷Lu-PSMA-617 or radium-223, and immunotherapy with ¹⁷⁷Lu-PSMA-617 or radium-223. Radiosensitizers may help increase the effect of radiopharmaceutical delivery, such as in the case of using olaparib. This includes the COMRADE study, which evaluated the combination of radium-223 plus olaparib vs radium-223 alone. Initial findings from COMRADE were presented by Rana R. McKay, MD, FASCO, at ASCO 2025 (abstract 5007).

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Radiation from radioligand therapy may also be used to create some inflammation that may increase the efficacy of immunotherapies. The EVOLUTION trial, which was presented at ASCO 2025 by Shahneen Sandhu, MBBS, FRACP, evaluated the combination of ipilimumab, nivolumab, and ¹⁷⁷Lu-PSMA-617 (abstract 5016). Moreover, work is being done on combining ¹⁷⁷Lu-PSMA-617 and de-escalated ²²⁵Ac-PSMA-617 to try to decrease the incidence of side effects associated with ²²⁵Ac-PSMA-617 while maintaining some coverage with ¹⁷⁷Lu-PSMA-617.