Report from the 2025 ASCO Genitourinary Cancers Symposium

NEJM Group was on hand to cover the 2025 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, held February 13 to 15 in San Francisco. Here, NEJM Journal Watch Oncology and Hematology Associate Editor Dr. Robert Dreicer reviews key trials in prostate cancer. Abstracts are available in the meeting proceedings.

In patients undergoing first-line treatment for metastatic castration-resistant prostate cancer, the addition of the poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor talazoparib to enzalutamide offers a long-term survival benefit over enzalutamide alone, according to final overall survival data from the industry-supported, phase 3 TALAPRO-2 trial (abstract LBA18).

Roughly 800 patients (unselected for homologous recombination repair [HRR] alterations) were randomized to enzalutamide (160 mg) plus either talazoparib (0.5 mg, or 0.35 mg if moderate renal impairment) or placebo once daily. All participants had an Eastern Cooperative Oncology Group (ECOG) performance-status score ≤1, were receiving ongoing androgen-deprivation therapy, and had not previously received life-prolonging therapy for castration-resistant prostate cancer. During a median follow-up of approximately 53 months, overall survival (OS) favored the talazoparib–enzalutamide group (hazard ratio for death, 0.796). Median OS was 46 months with talazoparib–enzalutamide versus 37 months with placebo–enzalutamide.

In a separate TALAPRO-2 cohort of 400 patients with HRR-deficient disease (abstract LBA141), OS again favored talazoparib–enzalutamide during a median follow-up of 44 months (hazard ratio, 0.622). Median overall survival was 45 months with talazoparib–enzalutamide versus 31 months with placebo–enzalutamide.

In both cohorts, updated radiographic progression-free survival (rPFS) data continued to show a benefit with talazoparib–enzalutamide. The most common grade 3–4 adverse events with the drug combination were anemia and neutropenia, consistent with earlier results.

Summary by Amy Herman, Staff Editor

COMMENT — Dr. Robert Dreicer

The results of this well-done study demonstrated a statistically significant and clinically meaningful improvement in both OS and rPFS in an unselected (for HRR alterations) population. The challenge is twofold: (1) the question of the utility of this approach in patients after taking androgen-receptor pathway inhibitors (ARPIs; essentially all patients were ARPI-naive), and (2) the regimen's toxicity profile.

Mevrometostat improves radiographic progression-free survival (rPFS) in patients receiving standard-of-care therapy for metastatic castration-resistant prostate cancer (mCRPC), according to a manufacturer-sponsored, phase 1/2, dose-expansion study (abstract LBA138). Mevrometostat is a potent, selective small-molecule inhibitor of the enhancer of zeste homolog 2 (EZH2) enzyme.

The study included 81 patients with mCRPC who showed evidence of progression and previously received abiraterone and up to one line of chemotherapy in any setting. Patients were randomized to receive oral mevrometostat (1250 mg twice daily on an empty stomach) plus enzalutamide (160 mg daily) or enzalutamide alone.

During a median follow-up of 9.6 months, the median rPFS — the primary endpoint — was 14.3 months in the mevrometostat group versus 6.2 months in those receiving enzalutamide alone. In patients with measurable disease at baseline, the objective response rate was also higher with mevrometostat (27% vs. 14%).

Grade 3 or higher treatment-emergent adverse events were observed in 54% of patients receiving mevrometostat plus enzalutamide (most commonly diarrhea, neutropenia, and sepsis) and in 43% of those receiving enzalutamide alone.

Summary by Christine Judge, Staff Editor

COMMENT — Dr. Robert Dreicer

The results of this relatively small, randomized phase 1/2 trial are of significant interest. They suggest the ability to mitigate androgen-receptor pathway inhibitor (ARPI) resistance with the addition of mevrometostat to enzalutamide, albeit with significant toxicity. This regimen (with a lower mevrometostat dose) is now being investigated in two manufacturer-sponsored, phase 3 registration trials: NCT06551324 and NCT06629779.

The 24-gene prostate cancer RT gene expression score (PORTOS) distinguished between patients with prostate cancer who benefited and those who did not benefit from dose escalation of radiation therapy, according to an analysis of two phase 3 studies (abstract 308).

Researchers calculated the PORTOS for biopsy samples taken from patients in NRG/RTOG 0126, a study that showed an overall benefit of dose escalation from 70.2 Gy to 79.2 Gy in definitive radiotherapy, and prostatectomy samples from patients in SAKK 09/10, which showed no overall benefit of postoperative dose escalation from 64 Gy to 70 Gy.

In both study groups, a low PORTOS was associated with no benefit from dose escalation, whereas a medium-to-high score in NRG/RTOG 0126 was associated with significantly less biochemical failure, and a high score in SAKK 09/10 was associated with significantly longer clinical progression-free survival.

PORTOS did not correlate with clinicopathologic variables in the trials or in two large real-world data sets but did correlate modestly with hypoxia and strongly with immune signatures and molecular subtypes in the real-world data.

Summary by Christine Sadlowski, Staff Editor

COMMENT — Dr. Robert Dreicer

While not yet ready to apply in the clinic, the potential use of molecular signatures to inform clinicians regarding the utility of escalating doses of radiotherapy is of significant interest. Ultimately, these findings could also inform the potential of radiotherapy dose de-escalation.

For patients with high-risk prostate cancer who undergo radiotherapy and long-term androgen-deprivation therapy (ADT), a return to normal testosterone levels is associated with increased likelihood of survival, according to a phase 3 trial (abstract 310).

Over 600 patients with high-risk prostate cancer were randomized to undergo pelvic radiotherapy plus either 18 or 36 months of ADT.

During a median follow-up of 17 years, 57% of the 18-month cohort and 44% of the 36-month cohort had testosterone levels that recovered to normal. Both 10-year and 15-year overall survival (OS) significantly favored those whose testosterone levels had normalized versus those whose levels had not (10-year OS: 76% vs. 55%; 15-year OS: 44% vs. 30%). The effects were seen in both the 18- and the 36-month cohorts. The researchers note that there was no significant difference in prostate cancer–related death between those whose testosterone levels normalized and those whose levels did not.

Summary by Kelly Young, Staff Editor

COMMENT — Dr. Robert Dreicer

There remains limited data regarding the timing of testosterone recovery from prospective studies of radiotherapy with ADT. This very interesting analysis indicates that those men whose serum testosterone recovers post-ADT have improved OS (without impact on prostate cancer–related death). This observation reminds us how important testosterone recovery is with regards to non–prostate cancer–related morbidities and suggests the potential to “advocate” for testosterone replacement in patients at some point post-treatment.