Relugolix in Patients With High-risk, Localized or Locally Advanced Prostate Cancer Who Are Candidates for Radical Prostatectomy.

Relugolix is approved in the United States (US) and Europe for the treatment of advanced prostate cancer.

The HERO trial enrolled patients with castration sensitive prostate cancer and compared their sustained castration rate at 48weeks to leuprolide. While the safety profile of the 2 agents was similar, relugolix achieved castrate levels of testosterone faster and provided a higher overall rate of castration. In the phase III HERO trial, relugolix demonstrated suppression of testosterone concentrations to castration levels in 96.7% of patients from Day 29 through 48 weeks, which was superior to leuprolide and resulted in a 54% lower risk of major adverse cardiovascular events. Relugolix also demonstrated superior efficacy to leuprolide for key secondary endpoints, including the cumulative probability of testosterone suppression to castrate levels (< 50 ng/dL) on day 4 and on day 15, PSA response (> 50% decrease) at day 15 with confirmation at day 29, the cumulative probability of testosterone suppression to profound castrate levels (< 20 ng/dL) on day 15, and mean FSH level at the end of week 24. Testosterone recovery was investigated in a subgroup of patients (n = 184): 54% of relugolix recipients versus 3% of leuprolide recipients had testosterone recovery to ≥ 280 ng/dL 90 days after completing 48 weeks of treatment.Relugolix was generally well tolerated in men with prostate cancer, with most adverse events being consistent with physiologic effects of testosterone suppression. Most adverse events were of grade 1 or 2 severity. In a phase II study comparing relugolix to degarelix the global health status, as assessed by EORTC-QLQ-C30, and sexual activity and hormonal treatment-related symptoms, as assessed by the EORTC-QLQ-PR25, were negatively affected during treatment in both groups. Within 12 wk after treatment discontinuation, sexual activity scores improved by a mean of 12.1 for relugolix and 6.6 for degarelix and hormonal treatment-related symptoms changed by a mean of -5.0 and -1, respectively. Similarly, AMS total and subscale scores (sexual, psychological, and somatic) worsened during treatment in both groups but after treatment discontinuation, the mean percentage change in AMS total scores was -15% in the relugolix group and -2.9% in the degarelix group.

The fast testosterone recovery with relugolix was associated with a rapid improvement in a range of castration-related symptoms on QoL measures.

Building upon the practice-changing evidence established by the PROTEUS trial, evaluating oral Relugolix as a perioperative backbone in high-risk patients candidate for radical prostatectomy offers distinct pharmacological, safety, and patient-centered advantages. While PROTEUS validated the clinical benefit of perioperative androgen receptor pathway modulation, Relugolix provides rapid and profound testosterone suppression without an initial surge, paired with a significantly lower cardiovascular risk profile and markedly accelerated post-treatment testosterone and Quality of Life (QoL) recovery compared to standard LHRH agonists. In the HEROIC trial, testing a 3-month neoadjuvant Relugolix induction phase prior to surgery followed by 6 months of adjuvant Relugolix (Arm A) versus immediate surgery followed by 6 months of adjuvant Relugolix (Arm B) addresses whether an all-oral GnRH antagonist strategy can reproduce perioperative oncological downstaging and improve Biochemical Recurrence-Free Survival (bRFS) while optimizing cardiovascular safety and patient recovery.