PROTEUS Data Support Perioperative Apalutamide Plus ADT as New SOC in High-Risk Localized Prostate Cancer

One year of perioperative apalutamide (Erleada) plus androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS) and pathologic response compared with placebo plus ADT in patients with high-risk localized or locally advanced prostate cancer (HR-LPC), meeting the dual primary end points of the phase 3 PROTEUS trial (NCT03767244).¹

Data presented during the plenary session of the 2026 ASCO Annual Meeting, and simultaneously published in the New England Journal of Medicine,² showed that by blinded independent central review (BICR), apalutamide plus ADT (n = 1057) reduced the risk of metastasis or death by 20% vs placebo plus ADT (HR, 0.80; 95% CI, 0.67-0.96; P = .02); investigator-assessed MFS was consistent (HR, 0.74; 95% CI, 0.62-0.87; P = .0004).

The regimen also led to a 9-fold improvement in the rate of pathologic complete response (pCR)/minimal residual disease (pCR/MRD) at radical prostatectomy (RP), at 8.9% (n = 94) vs 1.0% (n = 10) with placebo plus ADT (OR, 10.17; 95% CI, 5.27-19.64; P < .0001). More than half of the responses in the apalutamide arm were pCRs. An exploratory analysis of residual cancer burden corroborated the pCR/MRD finding, at 30.6% vs 11.7%, respectively (OR, 3.36; 95% CI, 2.67-4.23; P < .0001).

“PROTEUS is the first to demonstrate that 1 year of perioperative apalutamide and ADT significantly improves MFS, that the PROTEUS regimen [led to] a significant improvement in major pathological response [at prostatectomy], and that these positive results are supported by significant improvements in event-free survival [EFS] and a nearly 3-year delay in time to subsequent therapy,” said Mary-Ellen Taplin, MD, FASCO, who is a medical oncologist at Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts, and served as principal investigator of the trial.

Why is there an unmet need in high-risk localized prostate cancer?

Although RP is a curative-intent treatment for high-risk disease, more than half of patients with HR-LPC ultimately relapse and require subsequent therapy that carries added morbidity.³ Once distant metastases develop, the prognosis is poor, with a median time from the development of metastases to death of approximately 3 to 5 years.^4,5 The androgen receptor pathway inhibitor apalutamide is established in metastatic castration-sensitive⁶ and nonmetastatic castration-resistant⁷ disease and had demonstrated favorable activity in the neoadjuvant setting in phase 2 trials.⁸ Those findings supported the rationale to examine whether 1 year of perioperative apalutamide plus ADT vs placebo plus ADT, could improve pathologic response and long-term outcomes in this curative-intent setting, according to Taplin.

How was the phase 3 PROTEUS trial of perioperative apalutamide designed?

PROTEUS is the largest therapeutic trial conducted to date in localized prostate cancer, according to Taplin, enrolling 2109 patients across 18 countries between July 2019 and June 2022.¹ She added that eligible patients met NCCN criteria for high-risk disease, with specified positive-core-biopsy requirements based on Gleason score and were candidates for RP. Patients were randomly assigned 1:1 to apalutamide at a daily dose of 240 mg or placebo, each with investigator-chosen ADT. Systemic therapy was given for 6 months before and 6 months after RP, Taplin added, with a brief hold of apalutamide or placebo around the time of surgery. Randomization was stratified by nodal status (cN0 vs N1), Gleason score (7 vs 8 to 10), and geographic region (North America vs Europe vs rest of the world).

The dual primary end points—pCR/MRD and MFS—were assessed by BICR. Investigators defined major pathologic response as either pCR or minimal residual disease of 5 mm or less in organ-confined, node-negative disease. Because prostate-specific membrane antigen (PSMA)-PET had become the preferred staging modality by 2021, the protocol was amended to add PSMA-PET to a composite MFS measure; 70% of patients underwent PSMA-PET imaging.

“Secondary end points are key metrics of patient-derived benefits,” Taplin said. The secondary end points in hierarchical order were EFS, time to first subsequent therapy, time to distant metastasis by conventional or PSMA-PET imaging, no evidence of disease at 4 years, MFS by conventional imaging, and time to PSA-free survival with testosterone recovery.

Baseline characteristics were balanced: the median patient age was 66.0 years (range, 61-71), slightly more than 95% had a Gleason score of 8 to 10, approximately 40% had a baseline PSA above 20 ng/mL, roughly 35% had at least T3 disease, and about 12% had nodal disease. The median follow-up was 61.7 months at the data cutoff date of February 2, 2026.

How did apalutamide plus ADT affect EFS and time to next treatment?

EFS favored apalutamide plus ADT, with a median of 57.1 months vs 38.4 months, translating to a 29% reduction in the risk of an oncologic event or death (HR, 0.71; 95% CI, 0.63-0.80; P < .0001). The time to first subsequent therapy of any kind was a median of 74.2 months with apalutamide plus ADT vs 41.5 months with placebo plus ADT, signifying a nearly 3-year difference and a 35% improvement (HR, 0.65; 95% CI, 0.57-0.73; P < .0001). “Notably, for the apalutamide/ADT cohort, there was a 29% reduction in both subsequent ADT and adjuvant or salvage pelvic radiation,” Taplin said.

Time to distant metastasis by conventional or PSMA-PET imaging also favored apalutamide plus ADT, with a 32% reduction in risk (HR, 0.68; 95% CI, 0.55-0.83; P = .0002); 82.3% (95% CI, 80.0%-85.2%) of patients in the apalutamide arm were free of distant metastasis at 5 years vs 76.2% (95% CI, 73.2%-79.0%) of those in the placebo arm.

MFS by conventional imaging alone did not reach significance (HR, 0.84; 95% CI, 0.67-1.07; P = .15), ending the hierarchical testing sequence; this was attributed to a small number of events, driven in part by concomitant PSMA-PET evaluation in 70% of patients and by subsequent therapy that delayed conventional-imaging metastasis. “The fact that 87% in the apalutamide/ADT cohort were without metastasis by conventional imaging at 5 years is a very positive outcome for these patients,” Taplin noted. She added that testosterone recovered to at least 200 ng/dL in 81.6% and 83.0% of patients in the apalutamide and placebo arms, respectively, with a median time from end of treatment to recovery of 8.1 months vs 6.6 months.

What is the safety profile of perioperative apalutamide plus ADT?

All-grade treatment-related adverse effects (TRAEs) were comparable between arms, at 95.2% with apalutamide plus ADT and 93.8% with placebo plus ADT. Grade 3/4 TRAEs were higher with apalutamide plus ADT (27.5% vs 18.9%), as were TRAEs leading to dose reduction (11.2% vs 2.3%) and dose interruption (12.0% vs 4.4%). Among adverse effects of special interest, only skin rash, a known effect of apalutamide, was substantially more frequent in the apalutamide arm (all grade, 33.0%; grade ≥3, 5.9%) vs the placebo arm (15.3%; 0.3%); falls, ischemic heart disease, fractures, cerebrovascular events, seizure, and fatigue were broadly similar between the arms.

TRAEs leading to death occurred in 7 patients (0.7%) in the apalutamide arm and 1 (0.1%) in the placebo arm, with 5 of the 7 deemed related to surgery. After a protocol amendment that required cardiovascular risk and cardiology assessment in higher-risk patients at screening and 1 month before RP, no further treatment-related deaths occurred in either arm, which underscores the importance of patient selection, according to Taplin.

What do the PROTEUS results mean for high-risk localized prostate cancer treatment?

Taplin reported that additional analyses are planned, including a PROTEUS substudy that randomized 400 participants 3:1 to RP alone or the PROTEUS regimen plus RP, along with biomarker assessments and the correlation of major pathologic response with MFS. Taplin concluded that the regimen sets the bar for a new standard of care in HR-LPC.

Disclosures: Taplin disclosed receipt of honoraria from Amgen, Astellas Pharma, AstraZeneca, Axis Medical Education, Blue Earth Diagnostics, Carden Jennings, DAVA Pharmaceuticals, Flare Therapeutics, Geode Therapeutics, GlaxoSmithKline, Interpublic GIS, Janssen Ortho, Laekena, MJH Healthcare Holdings, Novartis, Pfizer, Physicians’ Education Resource, Research to Practice, and UpToDate. She serves in a consulting or advisory role for Astellas Pharma, AstraZeneca, BioNTech, Blue Earth Diagnostics, Flare Therapeutics, Geode Therapeutics, GlaxoSmithKline, Janssen Ortho, Laekena, Novartis, Pfizer, and UpToDate. Research funding was provided by Janssen Ortho (inst); and travel expenses were provided by Advanced Prostate Cancer Socierty, Prostate Cancer Foundation, and South West Prostate Cancer Symposium.

References

1. Taplin ME, Gleave M, Shore ND, et al. Perioperative (neoadjuvant and adjuvant) apalutamide + ADT vs placebo + ADT with radical prostatectomy in high-risk localized or locally advanced prostate cancer: final analysis of the PROTEUS phase 3 study. Presented at: 2026 ASCO Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract LBA1.
2. Taplin ME, Gleave M, Shore ND, et al. Perioperative apalutamide in high-risk localized prostate cancer. N Engl J Med. Published May 31, 2026. doi:10.1056/NEJMoa2603878
3. Stattin P, Fleming S, Brookman-May SD, et al. Population-based study of disease trajectory after radical treatment for high-risk prostate cancer. BJU Int. 2024;134(1):96-102. doi:10.1111/bju.16362 3
4. Xie W, Ravi P, Buyse M, et al. Validation of metastasis-free survival as a surrogate endpoint for overall survival in localized prostate cancer in the era of docetaxel for castration-resistant prostate cancer. Ann Oncol. 2024;35(3):285-292. doi:10.1016/j.annonc.2023.11.017
5. Stensland KD, Caram MEV, Herr DJ, et al. National long-term survival estimates after radical prostatectomy for prostate cancer. Urology. 2024;184:135-141. doi:10.1016/j.urology.2023.10.018
6. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Md. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307
7. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546
8. McKay RR, Xie W, Ye H, et al. Results of a randomized phase II trial of intense androgen deprivation therapy prior to radical prostatectomy in men with high-risk localized prostate cancer. J Urol. 2021;206(1):80-87. doi:10.1097/JU.0000000000001702