Congress highlights 2025

Advances continue to be made in all aspects of radiotherapy for prostate cancer. Here, we round up the discussions and key data from the 2025 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium, focusing on emerging biomarkers.

PORTOS can aid treatment decisions

The first symposium talk addressed the use of the Prostate Cancer Radiation Therapy Outcomes Score (PORTOS), formerly named the Post-Operative Radiation Therapy Outcomes Score, as a predictor of dose response to radiotherapy. In their research, Shuang (George) Zhao (University of Wisconsin, Madison, USA) and colleagues demonstrated that PORTOS has utility as a biomarker for benefit of radiotherapy dose escalation on biochemical failure, predicting response to both salvage radiation doses and definitive doses, as assessed in the SAKK09/10 and NRG/RTOG trials respectively.

Patients with localized prostate cancer and a lower PORTOS score did not benefit from the addition of post-operative radiotherapy, whereas patients with a higher score did. Higher PORTOS scores were also associated with an increased risk of adverse events after administration of dose escalation radiotherapy, compared with lower-dose radiation.

In combination with patient-specific factors and biology, PORTOS could be used to guide treatment decisions, sparing those least likely to benefit from the potentially increased toxicity risk associated with dose escalation, while tailoring radiation dosing for others. Zhao ended by acknowledging the contribution of his mentor Felix Feng, 1975–2024, who was one of the original developers of PORTOS.

ctDNA fraction is associated with clinical outcomes

Considering that PC can progress despite stable prostate-specific antigen (PSA), there is a real need for an expanded selection of biomarkers to support the management of this disease and improve patient outcomes.

Johann de Bono (Royal Marsden NHS Foundation Trust, London, UK) presented an exploratory analysis of data from the phase 3 PSMAfore trial, investigating the association of baseline and on-treatment circulating tumor DNA (ctDNA) fraction with clinical outcomes of taxane-naive patients with metastatic castration-resistant prostate cancer. In this trial, patients who experienced disease progression after androgen receptor pathway inhibitor (ARPI) therapy received treatment with either another ARPI or with lutetium-177-PSMA-617 (Lu-PSMA [prostate-specific membrane antigen]).

A higher ctDNA fraction on cycle 2 day 1 was associated with worse radiographic progression-free survival (rPFS) and overall survival (OS). Furthermore, early ctDNA fraction dynamics provided additional information in models of rPFS and OS beyond PSA.

These findings indicate that post-treatment changes in ctDNA fraction could have utility as a response biomarker, particularly in patients with tumor cells that are not PSMA-avid and could therefore be missed by PSMA-positron emission tomography (PET) scanning. Further evaluation of changes in ctDNA as an intermediate endpoint for clinical benefit is warranted.

PSMA-PET scans as a predictor of response

In his presentation discussing radiographic criteria to assess response after treatment, Danny Mena Cortes (Oncología San José de Sonora, Guaymas, Mexico) showed that using a mean standard PSMA uptake value with a cutoff of 10 on a PSMA-PET scan is a predictive biomarker of response.

PSMA-PET–CT scans could spare patients the inconvenience of bone scans, helping to make better treatment decisions. Cortes also recommended that dosimetry results should be integrated into the analysis of therapy response.

Advances continue to be made in all aspects of radiotherapy for prostate cancer. Here, we round up the discussions and key data from the 2025 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium, focusing on radiation therapy for metastases.

Radiation therapy reduces distant metastases

Standard-of-care (SOC) options for high-risk prostate cancer (PC) include radiotherapy with long-term androgen deprivation therapy (ADT), or radical prostatectomy (RP) with selective use of post-operative radiotherapy with or without ADT.

Previous analyses indicate that patients receiving radiotherapy plus ADT have higher mortality rates from other causes compared with patients undergoing surgery alone; however, this may be due to older age or a higher burden of comorbidity, and results differ when endpoints other than mortality are considered. In addition, many of these analyses have missing data or other confounding factors. Soumyajit Roy (Rush University Medical Center, Chicago, Illinois, USA) shared results of a meta-analysis of two trials (PUNCH and NRG/RTOG 0521) selected to reduce sources of bias.

Patients with high-risk PC had significantly lower incidence of distant metastases with a radiotherapy-based strategy compared with the RP approach (8-year inverse probability of treatment weighting cumulative incidence of 23% with surgery vs 16% with radiotherapy). Roy proposed that post-operative radiotherapy and ADT-docetaxel could narrow this gap.

Stereotactic body radiotherapy to oligometastatic sites can improve rPFS

Presenting data from the GROUQ-PCS 9 study, Tamim Niazi (McGill University, Montreal, Canada) and team showed that stereotactic body radiotherapy (SBRT) in combination with enzalutamide and ADT to oligometastatic sites in patients with metastatic castration-resistant prostate cancer (mCRPC) significantly improved radiographic progression-free survival (rPFS) by a median 2.3 years, with a 52% risk reduction.

This treatment regimen also improved biochemical PFS by a median of 1.5 years (with a 42% risk reduction), in addition to delaying the time to next therapy by a median 2.2 years (with a 58% risk reduction). These findings indicate that SBRT to oligometastatic sites may be beneficial and should be considered in patients with mCRPC.

Silke Gillessen (Università della Svizzera Italiana, Lugano, Switzerland) highlights how clinical findings presented at ASCO GU 2025 contribute to our evolving understanding of oligometastatic prostate cancer, and their implications on disease management. View transcript.

Metastases-directed therapy is beneficial across the oligometastatic disease spectrum

Chad Tang (The University of Texas MD Anderson Cancer Center, Houston, USA) presented results from WOLVERINE, a meta-analysis looking at individual patient data from five randomized controlled trials of metastases-directed therapy (MDT) added to SOC in oligometastatic PC. 

Results demonstrated significant benefit of MDT addition to SOC therapy for rPFS and castrate resistance-free survival, and a near-significant association with overall survival. MDT addition was beneficial across the entire oligometastatic PC disease spectrum ranging from de novo to metachronous and castration-sensitive PC to CRPC.

Advances continue to be made in all aspects of radiotherapy for prostate cancer. Here, we round up the discussions and key data from the 2025 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium, with a focus on emerging treatments and future targets.

Lu-PSMA added to enzalutamide

Looking to data from the PSMAfore study, Silke Gillessen (Università della Svizzera Italiana, Lugano, Switzerland) discusses the potential association between ctDNA fraction and clinical outcomes in patients with mCRPC. View transcript.

Louise Emmett (St Vincent’s Hospital, Sydney, Australia) presented secondary endpoint results from the ENZA-P trial of lutetium-177-prostate specific membrane antigen-617 (Lu-PSMA) added to enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC) and risk factors for early enzalutamide failure.

After a median follow-up of 34 months, overall survival was significantly longer with Lu-PSMA plus enzalutamide (n=83) than with enzalutamide alone (n=79; median 34 vs 26 months; HR, 0.55; 95% CI, 0.36–0.84; p=0.005).

Grade 3–5 adverse events (AEs) occurred in 46% of the Lu-PSMA plus enzalutamide group and 44% of the enzalutamide alone group. The most frequent grade 3 AEs were anemia, fatigue, decreased platelets (Lu-PMSA only), and decreased white cell count.

These data highlight the potential for PSMA-ligand radiotherapy to be administered with an androgen receptor pathway inhibitor more widely, and warrant further investigation in phase 3 trials.

Lu-PSMA synergistic combinations

Devaki Shilpa Surasi (The University of Texas MD Anderson Cancer Center, Houston, USA) talked about more synergistic Lu-PSMA combinations currently being explored for advanced prostate cancer. She gave a brief overview of encouraging indicators from ongoing phase 1/2 trials of Lu-PSMA with cabazitaxel (LuCAB), olaparib (LuPARP), pembrolizumab (PRINCE), ipilimumab plus nivolumab (EVOLUTION), and radium (AlphaBet).

In addition, the RALU study is investigating the efficacy of sequencing radiotherapies with radium as an alpha emitter followed by Lu-PSMA (a beta emitter). Surasi suggested that an alpha emitter could target micrometastases not being treated by beta emitters, and highlighted the crucial importance of balancing efficacy and toxicity of PSMA theranostics.

Mevrometostat with enzalutamide

Informed by the latest clinical data presented at ASCO GU 2025, Gillessen gives an overview of the evolving mCRPC treatment landscape and potential new therapies on the horizon. View transcript.

Mevrometostat is a potent and selective inhibitor of EZH2, a protein that is implicated in the development of mCRPC through multiple mechanisms and is associated with a poor prognosis in CRPC.

Michael Schwiezer (Fred Hutchinson Cancer Center, Seattle, Washington, USA) presented results from the open-label, randomized, dose-expansion phase of a study investigating the efficacy and safety of combining mevrometostat with enzalutamide in patients with mCRPC. The combination treatment resulted in improved outcomes versus enzalutamide alone, with a manageable adverse event profile.

The median radiographic progression-free survival was 14.3 months (95% CI, 7.5–not estimable) for the mevrometostat plus enzalutamide cohort and 6.2 months (4.1–13.9) for the enzalutamide cohort (HR, 0.51; 90% CI, 0.28–0.95).

The most common all-grade, treatment-emergent AEs were diarrhea (78.0%), decreased appetite (58.5%), and dysgeusia (58.5%) for mevrometostat plus enzalutamide, and asthenic conditions (42.5%), nausea (25.0%), and anemia (22.5%) for enzalutamide alone.

Pivotal phase 3 studies assessing the therapeutic benefit of mevrometostat in mCRPC are ongoing.

New targets for future therapies

William Kevin Kelly (Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA) reviewed some promising non-PSMA candidates for future targeted therapies. Several, such as CD46, delta-like protein DLL3, STEAP1, and hK2/KLK2, show high sensitivity, good correlation to tumor burden, and stable expression. The tumor microenvironment is also particularly rich in candidate targets, including fibroblast activation protein and carbonic anhydrase IX.

JNJ-69086420, an hK2-targeted, humanized monoclonal antibody, conjugated to actinium-225, has shown interesting initial results: upon binding to hK2 on cancer cells, it delivers alpha radiation to prostate cells, inducing tumor cell death.

Xaluritamig is a humanized bispecific antibody that targets STEAP1 and is designed to facilitate T-cell-mediated lysis of STEAP1-expressing cells. It demonstrates antitumor activity against both soft tissue and bone disease, and may have good durability of response.

During his presentation, Kelly highlighted that the challenges for novel targeted agents include a better understanding of tumor heterogeneity, lineage plasticity, and the functional relevance of targets. He also emphasized the clinical need for enhanced imaging, blood and/or urine-based monitoring, and relevant pre-clinical models.