Perioperative Apalutamide Shifts Standard in Localized, High-Risk Prostate Cancer

Treatment with apalutamide (Erleada) plus androgen-deprivation therapy (ADT), given for 6 months before and after surgery, reduced the risk for death or metastases by 20% vs placebo among patients with high-risk localized or locally advanced prostate cancer, according to the final analysis of the phase 3 PROTEUS (NCT03767244) study presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in the New England Journal of Medicine (NEJM).^1-2

Further, in the trial–which was the largest therapeutic trial in localized high-risk prostate cancer–patients were 9 times more likely to have little to no cancer remaining following their procedure with the doublet therapy, compared with placebo plus ADT.

“PROTEUS is the first to demonstrate that 1 year of perioperative apalutamide and ADT significantly improves metastasis-free survival, or MFS,” said Mary-Ellen Taplin, MD, FASCO, during a presentation of the data. “The PROTEUS regimen had a significant improvement in major pathologic response, and these positive results are supported by significant improvements in event-free survival, with a nearly 3-year delay in time to subsequent therapy.”

What did the final analysis of the PROTEUS study show?

After a median follow-up of 61.7 months, the percentage of patients with pathological complete response (pCR) or minimal residual disease (MRD) was 8.9% in the apalutamide group, compared with 1% with placebo (odds ratio [OR], 10.17; 95% CI, 5.27-19.64; P < .001).

Similarly, the MFS rate was higher with apalutamide, with a probability of 5-year MFS of 78.2% vs. 73.5%, respectively (HR, 0.80; 95% CI, 0.67-0.96; P = .02).

Lastly, secondary end points significantly favored the apalutamide regimen over placebo plus ADT (P < .001 for all between-group comparisons). Among patients who received 1 year of the apalutamide regimen, the time to needing subsequent therapy was significantly longer, compared with placebo (74.2 months vs 41.5 months), reducing the risk by 35% (HR, 0.65; 95% CI, 0.57-0.73; P < .0001).

Tamlin also noted that most patients also recovered adequate testosterone levels within 8.1 months of therapy with apalutamide following surgery. Further, patients in the apalutamide cohort experienced a 29% reduction in the risk of disease recurrence or death (HR, 0.71; 95% CI, 0.63-0.80; P < .0001) and improvements in time to distant metastasis (HR, 0.68; 95% CI, 0.55-0.83; P = .0002).

When assessed by residual cancer burden, MRD also improved with apalutamide compared with placebo (30.6% vs 11.7%; OR, 3.36; 95% CI, 2.67-4.23; P < .0001).

Grade 3 or 4 adverse effects (AEs) occurred in 39.6% of the patients in the apalutamide group and in 31.0% of those in the placebo group. According to the NEJM study, the difference between the groups was driven primarily by a higher incidence of rash in the apalutamide group.

“For decades, surgery has been the standard approach for many patients with high-risk localized or locally advanced prostate cancer, but these data suggest it may not be enough on its own,” Adam Kibel, MD, urologic surgeon and chair of the Department of Urology at Mass General Brigham, said in a press release.³ “Earlier integration of apalutamide has the potential to reshape how prostate cancer is treated by building on curative-intent surgical treatment and improving outcomes for these patients.”

How did the PROTEUS trial set a new standard in localized prostate cancer?

Taplin explained that, despite advancements made in radical prostatectomy, among those with high-risk disease, “more than half will relapse, incurring morbidity from subsequent therapy.”

Therefore, in the phase 3, double-blind, placebo-controlled trial, patients with newly diagnosed high-risk localized or locally advanced prostate cancer were randomized 1:1 to receive either ADT plus 240 mg apalutamide per day (n = 1057) or ADT plus placebo (n = 1052) for six 28-day cycles before and after radical prostatectomy with pelvic lymph-node dissection.

A composite of pCR/MRD (defined as a pathological stage of ypT2 or lower, with a tumor size of ≤5 mm in the greatest dimension) and MFS served as the co-primary end points.

“PROTEUS has a novel end point of major pathologic response and [metastasis-free survival (MFS)], measured both by conventional and PSMA PET imaging,” Taplin explained.

Secondary end points included EFS, first subsequent treatment, distant metastasis, and safety.

“This is the first convincing randomized control trial demonstrating improvement in clinically meaningful endpoints in patients with high-risk localized prostate cancer treated with radical prostatectomy. With [pCR ] rates near 9% and [MFS] improvements of 20% compared with [ADT] alone, the addition of apalutamide … clearly improves outcomes in surgical patients at high risk for relapse. That said, we haven’t yet compared it directly to current options like upfront surgery or the combination of radiation and androgen deprivation therapy,” William K. Oh, MD, Yale School of Medicine and an ASCO Expert in genitourinary cancers, said in a press release issued by the society.⁴

Taplin concluded by nothing that there was more to come with the addition of apalutamide to ADT. “We are excited for future analyses, including the substudy comparing PROTEUS [with] prostatectomy alone, extensive biomarker assessment, and correlation of major pathologic response with MFS.”

References

1. Taplin ME, Gleave M, Shore N, et al. Perioperative (neoadjuvant and adjuvant) apalutamide (APA) + androgen deprivation therapy (ADT) vs placebo (PBO) + ADT with radical prostatectomy (RP) in high-risk localized or locally advanced prostate cancer (HR LPC/LAPC): final analysis of the PROTEUS phase 3 study. Presented at: 2026 ASCO Annual Meeting; May 29 to June 2, 2026; Chicago, Illinois. Abstract LBA1
2. Taplin ME, Gleave M, Shore N, et al. Perioperative apalutamide in high-risk localized prostate cancer. N Eng J Med. Published online May 31, 2026. doi:10.1056/NEJMoa2603878
3. Johnson & Johnson’s phase 3 prostate cancer study shows ERLEADA® (apalutamide) before and after surgery significantly reduces risk of metastasis or death, breaking a decades-long treatment paradigm. News release. Johnson & Johnson. May 31, 2026. Accessed May 31, 2026. https://tinyurl.com/ywtds9k9
4. Potential new targeted treatment option for people with localized high-risk prostate cancer. News release. ASCO. May 31, 2026. Accessed May 31, 2026. https://tinyurl.com/ycxrpyn6