Evolving Standards in Prostate Cancer: Lessons From ESMO 2025 With Stephen Freedland, MD, and Murilo Luz, MD

Enza‑A: When an Active Drug Fails to Move the Needle

The Enza‑A trial, testing the addition of enzalutamide to androgen deprivation therapy (ADT) plus radiation in high‑risk localized prostate cancer, was one of the biggest surprises. Building on trials such as STAMPEDE, many expected a positive result; instead, Enza‑A showed essentially no benefit for adding enzalutamide in this setting.

Dr. Luz stressed this should not be interpreted as a failure of the drug itself: “We definitely shouldn’t expect that enzalutamide is not effective in localized prostate cancer.” Enzalutamide has proven benefit in biochemically recurrent, nonmetastatic castration‑resistant disease and metastatic castration‑sensitive disease. The issue is likely the enrolled population and excellent baseline outcomes: in the control arm, the 8‑year prostate cancer–specific mortality rate was only 4%.

As Dr. Freedland pointed out, when a trial is negative, the key question is whether it reflects “a bad drug” or “the wrong patient population,” and here the data strongly support the latter. Enza‑A thus serves as a reminder that even very active agents may not deliver additional benefit when applied to relatively low‑risk cohorts with low event rates.

New Triplets in mCSPC: Targeted, Not For All

In metastatic castration‑sensitive prostate cancer (mCSPC), ESMO 2025 showcased a more complex triplet landscape. Beyond the traditional ADT + androgen receptor pathway inhibitor (ARPI) + docetaxel backbone, newer approaches now include poly-ADP ribose (PARP) inhibitors, radiopharmaceuticals, and pathway‑targeted agents. “We are coming for the era of the new triplets,” Dr. Luz commented, emphasizing that these regimens will increasingly be defined by molecular and imaging biomarkers.

The AMPLITUDE trial exemplifies this transition, with a triplet of ADT, ARPI, and a PARP inhibitor in BRCA‑mutated patients. While not yet standard, its efficacy and reassuring quality‑of‑life data support biomarker‑restricted intensification in this subset.

The PSMA Addition trial, adding lutetium‑PSMA to ADT + ARPI as first‑line mCSPC therapy, generated intense interest. The trial met its primary end point, with a radiographic progression-free survival (rPFS) hazard ratio of about 0.75, but many found the effect size modest relative to expectations. “We had extremely high hopes,” Dr. Freedland noted, and the outcome felt “a little underwhelming,” particularly given the added toxicity of a third agent. Quality‑of‑life analyses showed more adverse events, with some toxicities, such as xerostomia, worsening six to eight months after randomization, suggesting cumulative harm once PSMA‑positive tumor burden has already been reduced.

These findings raise practical questions: Do all patients need six fixed cycles of lutetium‑PSMA, or could a response‑adapted strategy (eg, two cycles with the option to re‑expose later) maintain benefit while reducing long‑term toxicity? Dr. Luz wondered about using two cycles now and re-exposing the patient lutetium‑PSMA again in the future again, especially given its established role in the castration‑resistant setting. For now, he sees lutetium‑based triplets as an option for selected patients—such as those with high‑volume, PSMA‑expressing disease who are poor chemotherapy candidates—rather than a universal standard.

CAPItello and PTEN Loss: Validating a Biomarker‑Driven Triplet

The CAPItello trial, evaluating capivasertib added to ADT and abiraterone/prednisone in PTEN‑deficient metastatic disease, further underscores the rise of biomarker‑guided intensification. CAPELLO improved median rPFS from roughly 25 to 33 months in patients with PTEN loss by immunohistochemistry (IHC) using a 10% cutoff. While not transformative, this represents a meaningful benefit in a molecularly defined subgroup.

What particularly impressed Dr. Luz and Dr. Freedland were exploratory analyses showing a stronger effect with more profound PTEN loss. As PTEN expression fell below 10%, the magnitude of benefit increased, suggesting a clear biological gradient. For Dr. Freedland, this profile “really validates the biomarker, validates the pathway, and validates the drug; the question is now how to use that clinically.”

Implementing CAPItello-like strategies will require attention to testing logistics and cutoffs. PTEN IHC is not universally available and may not fully align with genomic measures of loss. In addition, given that benefit appears greatest at the lowest levels of PTEN expression, clinicians may ultimately opt for more stringent thresholds (eg, near‑complete PTEN loss) when considering capivasertib‑based triplets.

Conclusions from ESMO 2025

Across these data sets, a consistent message emerges: prostate cancer management is moving from empiric intensification to biomarker‑guided personalization, with important implications for everyday practice. Overall, the ESMO 2025 data clearly point toward a future in which treatment decisions hinge on matching the right intensity and the right triplet to the right patient—guided by robust biomarkers, thoughtful risk assessment, and specialized expertise.

Key Takeaways

• Intensification is not always beneficial. Enza‑A shows that adding an active ARPI to already effective local and systemic therapy may not improve outcomes when baseline risk is low, but this does not mean that enzalutamide is ineffective; patient selection is key.
• Doublet therapy remains foundational. For most patients with advanced disease, ADT plus an ARPI should still be considered standard; biomarkers are less relevant at this foundational step.
• Triplets should be selectively deployed. New triplets with PARP inhibitors, lutetium‑PSMA, or capivasertib offer incremental benefit in specific subgroups but have not yet delivered a “home run” in unselected populations. Rational use requires BRCA/HRR testing, PSMA PET (and potentially FDG PET), and PTEN assessment.
• Toxicity and duration matter. Fixed six‑cycle lutetium‑PSMA in mCSPC may overtreat some responders and contribute to late toxicity; response‑adapted strategies and careful patient selection will be key as the field matures.
• Complexity favors specialization. As options multiply, counseling becomes longer and more nuanced. In light of all the doublet and triplet options, referral to clinicians or multidisciplinary teams with knowledge of the nuances is critical.

About the Speakers

Stephen Freedland, MD, is a Professor of Urology and the Warschaw Robertson Law Families Chair in Prostate Cancer at Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center. He is also the Director of the Center for Integrated Research in Cancer and Lifestyle and the Associate Director for Education and Training at Samuel Oschin, and he holds a Staff Physician appointment at the Durham VA Medical Center in Durham, North Carolina. Dr. Freedland has published over 700 articles and served on numerous AUA and ASCO guideline panels for prostate cancer. His research interests include cancer health disparities, risk stratification, and the role of diet, lifestyle, and obesity in cancer.

Murilo Luz, MD, is an Assistant Professor of Urology at Mount Sinai in New York. He specializes in the treatment of urologic malignancies, including prostate, bladder, testis, penile, and kidney cancer. Dr. Luz also has experience in minimally invasive and robotic surgery. He serves as an investigator for clinical trials developing novel treatments for urologic malignancies.