Perioperative Apalutamide Cuts Metastasis Risk in Proteus Trial

Key Takeaways

• The PROTEUS trial met both primary endpoints, with higher pathologic response at surgery and improved metastasis-free survival for the combination regimen.
• Secondary analyses showed longer time before subsequent therapy and a broader pattern of delayed disease-control events with perioperative apalutamide plus hormone therapy.
• The adverse-event pattern was consistent with prior apalutamide experience, although adverse events and discontinuations were more frequent, and the regimen remains unapproved in this setting.

Johnson & Johnson announced final PROTEUS analysis results in the perioperative setting for newly diagnosed high-risk localized or locally advanced prostate cancer. Perioperative apalutamide plus androgen deprivation therapy around radical prostatectomy was associated with a lower risk of metastasis or death, with an MFS hazard ratio of 0.80. The phase 3 study also met its surgical pathology endpoint for pathologic complete response or minimal residual disease.

PROTEUS was a randomized, double-blind, placebo-controlled phase 3 trial that enrolled 2,109 newly diagnosed patients with high-risk localized or locally advanced prostate cancer who were candidates for radical prostatectomy. Patients with distant metastatic disease on conventional imaging were excluded under the protocol.

Participants were randomized to receive apalutamide 240 mg once daily plus ADT or placebo plus ADT for six months before surgery and six months after. Protocol therapy also included radical prostatectomy with pelvic lymph node dissection, and the dual primary endpoints were pCR/MRD and metastasis-free survival by blinded independent central review.

At a median follow-up of 61.7 months, the pCR/MRD rate was 8.9% with apalutamide plus hormone therapy and 1.0% with hormone therapy alone. The odds ratio was 10.17, with a 95% CI of 5.27-19.64 and p<0.0001. For metastasis-free survival, the hazard ratio was 0.80, with a 95% CI of 0.67-0.96 and p=0.02. Five-year MFS rates were 78.2% with the combination and 73.5% with hormone therapy alone. The final analysis showed gains in both surgical pathologic response and metastasis-free outcome measures.

Time to subsequent therapy was 74.2 months with apalutamide plus hormone therapy and 41.5 months with hormone therapy alone. The hazard ratio was 0.65, and event-free survival also favored the combination with an HR of 0.71. Time to distant metastasis showed an HR of 0.68, with a 95% CI of 0.55-0.83 and p=0.0002. Residual cancer burden rates were 30.6% versus 11.7%, with an OR of 3.36 and nominal p<0.0001. Most patients recovered adequate testosterone levels within 8.1 months.

The safety profile was consistent with previous apalutamide studies, with hot flush, urinary incontinence, erectile dysfunction, and rash among the highlighted adverse events. Grade 3 or 4 adverse events occurred in 39.6% of the apalutamide group and 31.0% of the hormone therapy alone group. Discontinuations due to adverse events occurred in 7.4% and 2.7%, respectively, while deaths were similar overall between arms. In the apalutamide group, more deaths were unrelated to prostate cancer, while the placebo group had more progression- or metastasis-related deaths.

Apalutamide plus hormone therapy is not yet approved in this perioperative setting, and additional analyses, including comparisons with surgery alone, are underway.