ASTRO response to the PROTEUS clinical trial

June 2, 2026 – Remarks from ASTRO’s Prostate Cancer Resource Panel Chair Amar Kishan, MD, and ASTRO President Neha Vapiwala, MD, FASTRO (also former chair of the panel):

“The results of the PROTEUS trial (NCT03767244) were recently presented at the American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in the New England Journal of Medicine. In this trial, 2,019 patients with high-risk or locally advanced prostate cancer were randomized to receive either 12 months of androgen deprivation therapy (ADT) and placebo with radical prostatectomy (RP) after the first six months, or 12 months of ADT and apalutamide (a potent, second-generation androgen receptor antagonist) with RP after the first six months.

The co-primary endpoints were (1) a pathologic complete response or minimal residual disease and (2) metastasis-free survival (MFS) on conventional imaging or prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT). Ultimately, with a median follow-up of 61.7 months, the percentage of patients with pathological complete response or minimal residual disease increased from 1.0% to 8.9% (p<0.001), while MFS increased from 73.5% to 78.2% (p=0.02).

Several important points remain critical to properly contextualize the results in multi-disciplinary discussions.

1. The trial did not include a standard of care control arm, as adding ADT to RP has previously never been shown to improve clinically meaningful outcomes in randomized trials.
   This is contrast to definitive radiotherapy for high-risk prostate cancer, where the standard of care for years has included the use of concomitant ADT based on multiple randomized trials showing not only an MFS benefit, but also an overall survival (OS) benefit.

2. Improvement in MFS is driven by the inclusion of metastatic events seen on PSMA PET/CT; in fact, the authors report that no significant between-group difference was observed in MFS assessed with conventional imaging alone.
   This is of importance for several reasons. First, while MFS assessed by conventional imaging is a known surrogate endpoint for OS, a biochemical recurrence-driven endpoint like event-free survival (EFS) does not display strong surrogacy for OS. Since PSMA PET/CT scans were triggered on PROTEUS at BCR and then done every 6 months, and ~60% of MFS events represent PSMA PET-based metastatic progression, PSMA MFS in this trial correlates more with EFS than conventional imaging MFS. The magnitude of MFS benefit seen in PROTEUS (with a HR of 0.80 by blinded central review, including PSMA-based events) falls significantly short of the surrogate threshold effect for EFS of 0.33. On a related note, intensification with a similar androgen pathway receptor inhibitor, enzalutamide, similarly failed to improve conventional imaging-based MFS when added to long-term ADT and definitive radiotherapy in the ENZARAD trial. Rather than being a conflicting result, this is actually consistent with the PROTEUS MFS-by-conventional imaging endpoint. 

3. Freedom from disease at four years was only 21.9% with ADT+apalutamide and 18.3% with ADT alone, suggesting many patients were not ultimately cured.
   Similarly, the eugonadal PSA-progression-free survival was 35.4 months in the apalutamide group and 30.3 months in the placebo group.

4. Despite the high recurrence rate, postoperative radiotherapy — a known curative treatment in this setting — appears to have been rarely utilized.
   It was only delivered in 26.6% of the ADT+apalutamide group and 36.8% of the ADT alone group.

5. Adverse events related to local therapy were not featured, but were reported in the manuscript and are relevant to discussions of upfront treatment strategy.
   Grade ≥2 urinary incontinence (spontaneous leakage, pads indicated or limited instrumental activities of daily living) rates were 27%. Grade ≥2 erectile dysfunction (intervention required) rates were ~27% and ~22%, respectively.

6. Serious adverse events during the treatment period were seen in 19.3% of patients receiving ADT and apalutamide, versus 16.4% receiving ADT.
   Serious events leading to death were seen in 0.7% vs. 0.1%, respectively.”