Perioperative Apalutamide in High-Risk Localized or Locally Advanced Prostate Cancer Reduces Risk of Metastasis and Death

High-risk localized and locally advanced prostate cancer patients treated with apalutamide — a next generation neoadjuvant androgen-receptor pathway inhibitor (ARPI) — plus hormone therapy before and after prostate cancer surgery resulted in more major pathologic responses and reduced the risk of metastasis or death, meeting both primary endpoints, in an international phase 3 clinical trial led by Adam Kibel, MD, chair of the Department of Urology at Mass General Brigham, and principal investigator Mary-Ellen Taplin, MD, medical oncologist at Dana-Farber Cancer Institute.

These potentially practice-changing findings were presented at a plenary session at the American Society for Clinical Oncology (ASCO) Annual Meeting in Chicago and published in the New England Journal of Medicine.

“As a urologic surgeon who cares for patients with advanced prostate cancer, I am thrilled by the significant improvements in pathology and metastasis-free survival we observed in the PROTEUS trial,” said Kibel, who is the senior author of the New England Journal of Medicine paper. “The outcomes of this trial have the potential to reshape the standard of care for our patients with high-risk prostate cancer.”

More than 330,000 people are diagnosed with prostate cancer annually, and up to 20 percent have an aggressive form of the disease that is considered high-risk for relapse after primary therapy. Current standard treatment includes radical prostatectomy and/or radiotherapy with androgen-deprivation hormone therapy (ADT). While this treatment works well for some, up to 50 percent of patients relapse within five years. This highlights the need for an improved regimen that acts earlier and more intensively to improve outcomes.

“Reducing the risk of prostate cancer recurrence and death with improved initial treatment regimens has been a longstanding unmet need for men with localized high-risk prostate cancer,” said Taplin. “The PROTEUS study was designed to help men whose cancer is still considered curable but has a high chance of recurring or spreading.”

PROTEUS is a randomized, double-blind, placebo-controlled phase 3 study that included 2,109 patients with newly diagnosed high-risk localized or locally advanced prostate cancer and is designed to evaluate the addition of apalutamide therapy before and after surgery. Apalutamide is approved for use in metastatic castration-sensitive prostate cancer and for nonmetastatic castration-resistant prostate cancer.

Participating patients orally received apalutamide plus ADT or a placebo plus ADT for six months before and after radical prostatectomy with pelvic lymph-node dissection. The study’s two primary endpoints included measuring the participant’s pathologic response and metastasis-free survival using both conventional imaging (bone scan and cat scan) and PSMA-PET imaging, a novel approach to measuring disease status. After a median follow-up of 61.7 months, the combination of apalutamide plus ADT resulted in a 20 percent reduced risk of metastasis or death with a five-year metastasis-free survival probability of 78.2 percent compared to 73.5 percent with hormone therapy alone. Patients treated with the apalutamide plus hormone therapy regimen were nine times more likely to have little-to-no cancer present at surgery, and 8.9 percent experienced a pathologic complete response or minimal residual disease, compared to 1.0 percent of patients who received hormone therapy alone. Strikingly, the study helped delay subsequent therapy by 33 months.

Side effects were consistent with data from previously reported studies.

“We have a paradigm-changing phase 3 clinical trial,” said Taplin. “This type of treatment regimen that combines systemic therapy with surgery is standard in other aggressive cancers and now has proven benefit for patients with high-risk localized or locally advanced prostate cancer.”

Authorship: In addition to Kibel and Taplin, authors include Martin Gleave, Neal D. Shore, Angela Lopez-Gitlitz, Alexander Kretschmer, Eleni Efstathiou, Paul L. Nguyen, Ronaldo Damião, Toshiyuki Kamoto, Ashley Ross, Alberto Briganti, Boris A. Hadaschik, Axel Heidenreich, Alvaro Juárez Soto, Huihui Ye, Geoffrey Gotto, Brendan Rooney, Shaozhou Ken Tian, Lisa Wetherhold, Branko Miladinovic, Sharon A. McCarthy, and Christopher P. Evans.

Disclosures: Kibel reports consulting/advisory roles with Advantagene, Bristol Myers Squibb, Candel Therapeutics, and Cellvax; honoraria from Johnson & Johnson, Merck, Profound, and Tolmar; and research funding from Pfizer. Additional author disclosures can be found at nejm.org.

Funding: Funding provided by Johnson & Johnson.

Paper cited: Taplin ME et al. “Perioperative Apalutamide in High-Risk Localized Prostate Cancer” NEJM DOI: 10.1056/NEJMoa2603878