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CHICAGO — Men with high-risk localized or locally advanced prostate cancer who received apalutamide plus androgen deprivation therapy (ADT) before and after radical prostatectomy were significantly more likely to achieve deep pathologic responses and less likely to develop metastatic disease than those who received ADT alone, according to the phase 3 PROTEUS trial.

Adding apalutamide to ADT reduced the risk for distant metastasis or death by 20%, translating into an absolute improvement in 5-year metastasis-free survival of about 5 percentage points (78.2% vs 73.5%). 

The findings “support the perioperative use of apalutamide plus ADT as a new standard of care for patients with localized high-risk prostate cancer,” said lead investigator Mary-Ellen Taplin, MD, a prostate cancer specialist at the Dana-Farber Cancer Institute in Boston who presented the findings at the American Society of Clinical Oncology annual meeting. The trial results were published simultaneously in the New England Journal of Medicine. 

“This is the first convincing randomized trial demonstrating improvement in clinically meaningful endpoints” by adding systemic therapy to surgery, said study discussant William Oh, MD, a genitourinary oncologist at Yale University in New Haven, Connecticut.

While the findings could help reshape treatment for high-risk surgical patients, the trial did not address whether perioperative therapy is necessary for all men and how the perioperative apalutamide approach compares with other standards such as radiation plus ADT and radical prostatectomy alone, Oh noted.

Inside Proteus

Radical prostatectomy is potentially curative in patients with high-risk localized or locally advanced prostate cancer but about half of patients relapse within 5 years. 

Previous trials have shown that, in metastatic, castration-sensitive

prostate cancer, ADT plus apalutamide led to improved overall survival compared with ADT plus placebo.

Taplin and colleagues conducted the PROTEUS trial to assess whether a perioperative approach with apalutamide and ADT could also benefit patients with high-risk localized or locally advanced prostate cancer undergoing radical prostatectomy.

In the phase 3 trial, the researchers randomly assigned 2109 patients from 118 hospitals worldwide to either perioperative apalutamide plus ADT or placebo plus ADT. The median age of participants was 66 years, and over 95% of men had a baseline Gleason score of at least 8.

Overall, 1057 patients received apalutamide (240 mg daily) plus ADT, while 1052 received ADT plus placebo in six 28-day treatment cycles 6 months before and 6 months after surgery. D istant metastases were identified using prostate-specific membrane antigen (PSMA) PET or conventional imaging.

Pathological complete response or minimal residual disease — defined as residual tumor no larger than 5 mm — was significantly higher in the apalutamide arm: 8.9% vs 1% (odds ratio, 10.17; P < .001). 

Metastasis-free survival at 5 years was higher in the apalutamide group: 78.2% vs 73.5% (hazard ratio [HR] for distant metastasis or death, 0.80; P = .02). In an exploratory subgroup analysis, however, the metastasis-free survival benefit was not statistically significant among patients assessed with conventional imaging alone (HR, 0.84; 95% CI, 0.67-1.07).

Several secondary outcomes favored apalutamide plus ADT. Event-free survival was almost 19 months longer in the apalutamide group — 57.1 months vs 38.4 months (HR, 0.71; P < .001) — and time to first subsequent local or systemic therapy was nearly 33 months longer (74.2 vs 41.5 months; HR, 0.65; P < .001). Additionally, a slightly higher percentage of patients receiving apalutamide had no evidence of disease at 4 years (21.9% vs 18.3%; odds ratio, 1.25).

The benefits came at a cost of more adverse events (AE) of all grades (37.9% with apalutamide + ADT vs 20.4% with placebo + ADT) and grade 3-4 AEs (8.6% vs 2.2%). The most common AEs in the apalutamide arm were skin rash (33% all grade) and fatigue (27.7%). Treatment-related AEs leading to death were also higher in the apalutamide group — 7 deaths (0.7%) vs 1 death (0.1%). 

Overall, though, Taplin concluded that the findings demonstrate “a breakthrough in a decades-long treatment paradigm by showing that the use of apalutamide earlier can deepen responses and significantly reduce the risk of cancer spreading or progressing.”

In an accompanying editorial, Emmanuel S. Antonarakis, MD, said ADT plus apalutamide “would represent the first option” for neoadjuvant and adjuvant systemic therapy for patients with high-risk localized or locally advanced prostate cancer, “marking a watershed moment for the field.” If this regimen is approved, these patients would have two broad treatment options: primary radiotherapy with 18 to 24 months of ADT, or radical prostatectomy with 12 months of perioperative ADT plus apalutamide, explained Antonarakis, with Masonic Cancer Center, University of Minnesota, Minneapolis. 

However, both Antonarakis and Oh noted that the trial leaves several important questions unanswered, including whether all patients require both preoperative and postoperative treatment and how the PROTEUS approach compares with other curative-intent strategies. Antonarakis also questioned the appropriateness of the control group, given that the current surgical standard for patients with high-risk prostate cancer is radical prostatectomy alone.

To that end, Taplin noted that results from a companion study directly comparing upfront surgery with the PROTEUS regimen are expected later this year.

PROTEUS was funded by Johnson & Johnson, maker of apalutamide. Among other industry ties, Taplin is an advisor for J&J subsidiary Janssen-Ortho and disclosed honoraria and research funding from the company. Investigators also included several J&J employees. Oh is an advisor for Abbott Diagnostics, AstraZeneca, Novartis, and Pfizer, among other industry relationships.