Juan Gómez Rivas, Associate Professor at Complutense University of Madrid, shared a post on X:
“Is the PROTEUS trial practice-changing? Or should we be more cautious?
For the first time, a phase III trial demonstrated that perioperative treatment with apalutamide plus androgen deprivation therapy improves pathological response and metastasis-free survival in men with high-risk localized prostate cancer undergoing radical prostatectomy.
Some key reflections:
- A landmark study. PROTEUS provides proof of concept that intensified perioperative systemic therapy can modify the biology of localized prostate cancer and potentially reshape future treatment paradigms.
- A modest absolute benefit. While statistically significant, the absolute improvement in 5-year metastasis-free survival was relatively small. This highlights the need to carefully balance efficacy against toxicity, cost, and the risk of overtreatment.
- An innovative but challenging endpoint. PROTEUS is the first randomized phase III trial to include PSMA-PET-detected metastases within its primary metastasis-free survival endpoint. This reflects modern imaging practice, but PSMA-PET-based MFS has not yet been validated as a surrogate for overall survival. As our imaging becomes more sensitive, we must ensure that our clinical endpoints remain meaningful for patients.
- Patient selection remains the key question. High-risk prostate cancer is not a single disease. The future lies in identifying the patients who truly benefit from treatment intensification through better biological and molecular stratification, rather than applying a ‘one-size-fits-all’ approach.
PROTEUS is undoubtedly a landmark trial. However, its greatest contribution may not simply be demonstrating that ‘more treatment is better,’ but rather opening the door to a more nuanced discussion about who should receive intensified therapy, how we should measure success, and how we can personalize treatment for patients with high-risk localized prostate cancer.”
Jeff Ryckman, Associate Professor of Radiation Oncology at WVU Medicine Camden Clark Medical Center, replied to Juan Gómez Rivas’s post, adding:
“Did you routinely give ADT in context of prostatectomies prior to this study?
The OP captures much of the editorial’s caution, but misses what I think is the key comparator issue that the editorial explicitly raises. PROTEUS did not test perioperative ADT/Apa vs modern SOC. The control arm was RP + perioperative ADT/placebo, not RP-first with early SRT/ADT as needed or upfront RT/ADT. So the trial shows apalutamide improves outcomes when added to perioperative ADT around RP. It does not show that the whole perioperative systemic intensification strategy beats local-first care.”
Title: PROTEUS Trial the Day After: Practice Changing or Premature Escalation?
Authors: Isabel Heidegger, Chiara Mercinelli, Giulia Marvaso, Jean Cristophe Bernhard, Elena Castro, Tamás Fazekas, Giorgio Gandaglia, Juan Gomez-Rivas, Guillaume Ploussard, Maria Rosaria Raspollini, Lara Rodriguez-Sanchez, Francesco Sanguedolce, Roderick van den Bergh, Morgan Rouprêt, Alessandro Volpe, Gianluca Giannarini, Pierre Blanchard
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PROTEUS Trial the Day After: Practice-Changing or Premature Escalation?
