<p>As more treatments become available for patients with metastatic prostate cancer, a more personalized selection of therapy may be possible based on an individual’s specific genomic- and tumor-related factors. Several studies presented at the <strong>2025 ASCO Annual Meeting</strong> focused on prognostic biomarkers that may help guide treatment decision making.</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>

I was the second author on the AMPLITUDE trial abstract, which was presented by Gerhardt Attard, MD, PhD, at ASCO 2025 (abstract LBA5006). AMPLITUDE enrolled patients with metastatic hormone-sensitive prostate cancer (mHSPC) with HRR gene alterations. Approximately half of these patients had BRCA1/2 mutations. The patients with BRCA mutations tend to have the best responses. A challenge with PARP inhibitor trials is that it is difficult to glean statistically significant efficacy in small subgroups of patients with other HRR gene alterations. In the AMPLITUDE trial, the radiographic progression-free survival end point was met, both in the BRCA1/2 subgroup and in all HRR mutation–positive patients. This was the first biomarker-selected, patient population–based phase 3 trial in mHSPC that met its primary end point. The overall survival (OS) trends were favorable, so I think that it is practice changing. In addition, niraparib was well tolerated, and its safety profile was manageable. The adverse events of niraparib were what you would expect, and no new safety signals came out.

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I want to emphasize that next-generation sequencing (NGS) is not being done frequently enough in the real world. I was a coauthor on a US retrospective cohort analysis that was published last year that found that only 27.1% of patients with metastatic prostate cancer underwent NGS testing of their tumors. I find this unacceptable because molecularly targeted therapies such as pembrolizumab (for patients with a high tumor mutational burden or microsatellite instability-high–positive patients) and olaparib (for HRR gene mutation–positive patients) were US Food and Drug Administration (FDA) approved for metastatic castration-resistant prostate cancer in 2017 and 2020. All patients with newly diagnosed metastatic prostate cancer should undergo both germline and tumor genomic testing.

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A very interesting abstract was presented at ASCO 2025 by Wolfgang Peter Fendler, MD, from the PROMISE Registry Group (abstract 266). Prostate-specific membrane antigen positron emission tomography (PSMA PET) scan–based prognostic nomograms were able to prognosticate OS risk groups across all stages of prostate cancer at least as well as—and maybe even better than—traditional risk factors such as pathology, Gleason grade, and the extent of the tumor. The PSMA PET scan has the potential to go beyond selecting patients for ¹⁷⁷Lu-PSMA-617 therapy to assist in prognosticating different stages of prostate cancer.

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Artificial intelligence (AI)–derived prognostication models based on digital pathology may help both as a prognostic tool and, potentially, in personalizing treatment strategies, as discussed in a study presented by Chien-Kuang Cornelia Ding, MD, PhD, at this year’s ASCO meeting (abstract 5106). Multimodal AI models are also being developed that go beyond pathology slides to also incorporate imaging studies and clinical, genomic, and laboratory data. As indicated in a study presented by Nicholas David James, PhD, FRCP, MBBS, at ASCO 2025, the time is coming when we might be able to give this information to a multimodal AI model to prognosticate and help us with treatment selection and clinical decision making (abstract 5001). I think that multimodal AI is going to allow us to better treat our patients.

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A prostate-specific antigen (PSA) response of less than 0.2 ng/mL 6 to 10 months after starting systemic therapy with ADT plus ARPI therapy is associated with improved survival based on clinical trial data. The results from an analysis of the IRONMAN registry, which includes more than 1200 patients with mHSPC, were presented by Michael Ong, MD, BSc, FRCPC, at ASCO 2025 (abstract 5002). The authors found that the PSA response after starting ADT and ARPI therapy is associated with positive survival outcomes. For example, the 3-year OS in patients who achieved a PSA of 0.02 to 0.2 ng/mL at 12 months was 80%. And, in patients who did not achieve a PSA level of 0.2 ng/mL or less, the 3-year OS was only 45.3%.

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These data add to the rationale for taking treatment breaks to minimize the long-term side effects associated with low testosterone levels in patients who achieve a PSA level of 0.2 ng/mL or less. Multiple trials have already started along those lines. For instance, the phase 3 EORTC GUCG 2238 De-Escalate trial and the phase 3 LIBERTAS trial have started and are randomizing patients with metastatic prostate cancer to continue standard therapy or receive intermittent therapy if they achieve a PSA of less than or equal to 0.2 ng/mL or less than 0.2 ng/mL, respectively.

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Patients who do not achieve a PSA of 0.2 ng/mL or less may need treatment intensification earlier on. As discussed by Dr Ong in another presentation at ASCO 2025, the phase 3 TRIPLE-SWITCH (SWOG/CCTG-PR26) trial is randomizing patients with mHSPC who do not achieve a PSA of 0.2 ng/mL or less to continuation with ADT and ARPI therapy vs continuation with ADT and ARPI therapy plus up to 6 cycles of docetaxel chemotherapy (abstract TPS5129). I think that we are coming into an era in prostate cancer treatment where we may potentially use PSA as a response biomarker and to help select treatments for these patients, which is pretty exciting.