<p>The number of available therapies for metastatic prostate cancer has expanded in recent years, and ongoing clinical trials continue to evaluate novel therapies alone and in combination. Researchers presented the results from a number of studies evaluating novel strategies and therapies for metastatic prostate cancer at the recent <strong>2025 ASCO Annual Meeting</strong>.</p> <p><br></p> <p><em>Following these presentations, featured expert Neeraj Agarwal, MD, FASCO, was interviewed by </em>Conference Reporter<em> Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Agarwal on these findings are presented here.</em></p>

Although PARP inhibitor treatment as monotherapy may not always have activity in patients with metastatic castration-resistant prostate cancer (mCRPC), there may be greater activity when you combine PARP inhibitors with agents such as ARPIs or radium-223. At ASCO 2025, we saw data presented by Rana R. McKay, MD, FASCO, from the phase 2 COMRADE trial evaluating the combination of olaparib and radium-223 vs radium-223 alone in patients with CRPC with bone metastases (abstract 5007). There was a very intriguing efficacy signal even in those without HRR gene alterations. Although a phase 2 trial is not yet going to change clinical practice, it reinforces my belief that PARP inhibitors have widespread potential when combined with other agents.

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KLK2 is widely expressed in prostate cancer cells, similar to STEAP1. The bispecific T-cell engager pasritamig (also known as JNJ-78278343), which targets KLK2, is being evaluated in a phase 1 trial that was presented by Capucine Baldini, MD, PhD, at this year’s ASCO meeting (abstract 5017). I am excited about this bsAb, and that excitement stems from the fact that the radiographic progression-free survival in patients with heavily treated mCRPC was 7.9 months with pasritamig, and it was pretty well tolerated. Some major issues that we have seen with bispecific T-cell engagers are that they can induce cytokine release syndrome and most patients require hospitalization for administration. While on pasritamig, patients did not experience greater than grade 1 cytokine release syndrome. KLK2 also provides the potential for combinations with other targeting agents, such as ¹⁷⁷Lu-PSMA-617. Since this has a different target, the rationale for combination is stronger than it would be if the agents were against the same target.

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Ultimately, our dream is to have therapies for advanced or metastatic prostate cancer that will allow for real breaks in treatment once disease stabilization has been achieved so that there is disease control without ongoing treatment. That is a goal for prostate cancer, and we do see some hint of that in the data from the EVOLUTION trial, which was presented at ASCO 2025 by Shahneen Sandhu, MBBS, FRACP (abstract 5016). EVOLUTION evaluated the combination of ¹⁷⁷Lu-PSMA-617 with ipilimumab and nivolumab vs ¹⁷⁷Lu-PSMA-617 alone. While ¹⁷⁷Lu-PSMA-617 with ipilimumab and nivolumab was associated with improved prostate-specific antigen progression-free survival at 12 months, 4 people developed myocarditis, which is a very toxic outcome. The next steps for the investigators are to determine how to avoid myocarditis and how to select patients who are likely to have long-term responses that allow for treatment discontinuation.

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Another novel target in mCRPC is B7-H3, which is heavily expressed in prostate cancer tumors and has lower expression in normal tissue. Data from a phase 1/2 trial evaluating an ADC targeting B7-H3 called DB-1311/BNT324 was presented at ASCO 2025 by Andrew Ohyama Parsonson, FRACP, MBBS (abstract 5015). This novel ADC was associated with fairly good efficacy and had an unconfirmed objective response rate of 27.9%, which is encouraging in heavily pretreated patients. Discontinuation rates were very low, and toxicities were manageable. These data provide a rationale for a phase 3 trial.

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¹⁷⁷Lu-PSMA-617 is already available in the clinic in the mCRPC setting based on data from the VISION trial. Recently, the US Food and Drug Administration (FDA) approved ¹⁷⁷Lu-PSMA-617 for patients with mCRPC who have not received prior chemotherapy, with the goal of delaying chemotherapy based on the results from the PSMAfore trial. The PSMAddition trial is evaluating patients with newly diagnosed metastatic hormone-sensitive prostate cancer who are treated with ADT plus AR-directed therapy and ¹⁷⁷Lu-PSMA-617 vs hormone therapy alone. We look forward to the presentation of these data at an upcoming meeting.

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Based on these data, ¹⁷⁷Lu-PSMA-617 may move to an earlier line of therapy in patients with metastatic hormone-sensitive prostate cancer, and it has the potential to be combined with other classes of treatment. For example, it can potentially be combined with ICIs, PARP inhibitors, AR degraders, or possibly even therapies targeting B7-H3. The scope is unlimited because of their nonoverlapping targets.

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However, we need to improve the availability of prostate-specific membrane antigen positron emission tomography scans and the multidisciplinary approach for patients with metastatic prostate cancer. Urologists, medical oncologists, radiation oncologists, and nuclear medicine physicians will have to come together to maximize the availability of ¹⁷⁷Lu-PSMA-617 in the real-world setting.