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Efficacy and Safety of Radiotherapy Plus Relugolix in Men With Localized or Advanced Prostate Cancer

  • Daniel E. Spratt,
  • Daniel J. George,
  • Neal D. Shore,
  • Michael S. Cookson,
  • Daniel R. Saltzstein,
  • Ronald Tutrone,
  • Alberto Bossi,
  • Bruce A. Brown,
  • Sophia Lu,
  • Mark Fallick,
  • Sarah Hanson,
  • Bertrand F. Tombal


Combination androgen deprivation therapy (ADT) with radiotherapy is commonly used for patients with localized and advanced prostate cancer.


To assess the efficacy and safety of the oral gonadotropin-releasing hormone antagonist relugolix with radiotherapy for treating prostate cancer.

Design, Setting, and Participants

This multicenter post hoc analysis of patients with localized and advanced prostate cancer receiving radiotherapy in 2 randomized clinical trials (a phase 2 trial of relugolix vs degarelix, and a subset of the phase 3 HERO trial of relugolix vs leuprolide acetate) included men who were receiving radiotherapy and short-term (24 weeks) ADT (n = 103) from 2014 to 2015 and men receiving radiotherapy and longer-term (48 weeks) ADT (n = 157) from 2017 to 2019. The data were analyzed in November 2022.


Patients receiving short-term ADT received relugolix, 120 mg, orally once daily (320-mg loading dose) or degarelix, 80 mg, 4-week depot (240-mg loading dose) for 24 weeks with 12 weeks of follow-up. Patients receiving longer-term ADT received relugolix, 120 mg, orally once daily (360-mg loading dose) or leuprolide acetate injections every 12 weeks for 48 weeks, with up to 90 days of follow-up.

Main Outcomes and Measures

Castration rate (testosterone level <50 ng/dL [to convert to nmol/L, multiply by 0.0347) at all scheduled visits between weeks 5 and 25 for patients receiving short-term ADT and weeks 5 and 49 for patients receiving longer-term ADT.


Of 260 patients (38 Asian [14.6%], 23 Black or African American [8.8%], 21 Hispanic [8.1%], and 188 White [72.3%] individuals), 164 (63.1%) received relugolix. Relugolix achieved castration rates of 95% (95% CI, 87.1%-99.0%) and 97% (95% CI, 90.6%-99.0%) among patients receiving short-term and longer-term ADT, respectively. Twelve weeks post–short-term relugolix, 34 (52%) achieved testosterone levels to baseline or more than 280 ng/dL. Ninety days post longer-term ADT, mean (SD) testosterone levels were 310.5 (122.4) (106.7) ng/dL (relugolix; n = 15) vs 53.0 ng/dL (leuprolide acetate; n = 8) among the subset assessed for testosterone recovery. Castration resistance-free survival was not statistically different between the relugolix and leuprolide acetate cohorts (hazard ratio, 0.97; 95% CI, 0.35-2.72; P = .62). Adverse events grade 3 or greater for short-term or longer-term relugolix (headache, hypertension, and atrial fibrillation) were uncommon (less than 5%).

Conclusions and Relevance

The results of these 2 randomized clinical trials suggest that relugolix rapidly achieves sustained castration in patients with localized and advanced prostate cancer receiving radiotherapy. No new safety concerns were identified when relugolix was used with radiotherapy.

Commentary by Dr. Constance Thibault

Androgen deprivation therapy (ADT) combined with radiotherapy is a cornerstone treatment for localised and advanced prostate cancer. The efficacy of ADT in improving survival is well-established, but traditional GnRH agonists raise concerns due to the initial testosterone surge, potential cardiovascular risks, and delayed testosterone normalisation post-treatment.


Relugolix offers a promising alternative by providing rapid testosterone suppression without the surge, potentially improving the safety and efficacy of prostate cancer treatment when combined with radiotherapy. This multicentre post hoc analysis incorporated data from patients with localised and advanced prostate cancer participating in two randomised clinical trials (a phase 2 trial comparing relugolix (120mg, orally once daily after a 320-mg loading dose on D1) vs. degarelix and a subset of the phase 3 HERO trial comparing relugolix vs. leuprolide acetate). The study included patients undergoing short-term (24 weeks, n=103) and longer-term (48 weeks, n=157) ADT in conjunction with radiotherapy, analysing data up to November 2022. Relugolix demonstrated high efficacy in achieving and maintaining castration levels of testosterone (<50 ng/dL) across both short-term and longer-term ADT durations, with castration rates of 95% and 97% respectively. Furthermore, relugolix facilitated faster testosterone recovery post-treatment compared to traditional ADT agents, with 52% of patients returning to baseline testosterone levels or higher after short-term ADT within 12 weeks vs 16% with degarelix. The safety profile of relugolix was favourable, with less than 5% of patients experiencing grade 3 or higher adverse events.


The findings suggest that due to its rapid action, effective maintenance of castration levels, and favourable safety profile, relugolix is a potential new standard of care for patients requiring ADT. This approach could improve patient outcomes by reducing the risks associated with traditional ADT agents and facilitating quicker hormonal recovery, thereby enhancing the overall quality of life for men with prostate cancer.