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

Abstract

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

Objective: 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.

Interventions: 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.

Results: 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.

Figure 1.. Patient Identification

Identification of patients included in this post hoc analysis from 2 randomized clinical trials: patients receiving short-term (24 weeks) androgen deprivation therapy (ADT) plus radiotherapy who received relugolix or degarelix (A) and longer-term (48 weeks) ADT plus radiotherapy who received relugolix or leuprolide acetate (B).

Figure 2.. Secondary End Points Associated With Testosterone, Prostate-Specific Antigen (PSA), and Follicle-Stimulating Hormone (FSH) Levels in Patients Treated With Androgen Deprivation Therapy (ADT) Plus Radiotherapy

Secondary end points associated with testosterone (to convert to nmol/L, multiply by 0.0347), PSA, and FSH levels in patients with prostate cancer receiving short-term ADT (24 weeks) (A) and longer-term ADT (48 weeks) (B) with radiotherapy. Dark blue bars represent relugolix across both panels, the medium blue bars represent degarelix, and the light blue bars represent leuprolide acetate. ^aFSH normal values for adults: 1.5-12.4 mIU/mL (to convert to IU/L, multiply by 1).

Figure 3.. Testosterone Levels Over Time in Patients Treated With Androgen Deprivation Therapy (ADT) Plus Radiotherapy

Time to testosterone (T) suppression (<50 ng/dL; to convert to nmol/L, multiply by 0.0347) and time to testosterone recovery (baseline or >280 ng/dL) in patients treated with relugolix or degarelix for 24 weeks plus radiotherapy (A) and time to testosterone suppression (<50 ng/dL) and time to testosterone recovery (≥50 ng/dL) in patients treated with relugolix or leuprolide acetate for 48 weeks plus radiotherapy (B). 50 ng/dL = castrate level; 280 ng/dL = lower limit of normal range. A subset of patients (relugolix [n = 15]; leuprolide acetate [n = 8]) in the HERO radiotherapy subgroup was assessed for testosterone recovery for up 90 days post treatment cessation. At the 90-day follow-up, testosterone levels were reported for 14 of 15 patients in the relugolix cohort. ^aTime to castration-free survival was defined as the number of days from the first dose to the first testosterone measurement of less than 50 ng/dL. If a patient had all post–first dose testosterone measurements 50 ng/dL or greater, the patient’s time to castration was censored at the last testosterone measurement that was 50 ng/dL or greater. Censorship was defined as the patient initiated an alternate ADT without recovery at the last testosterone laboratory assessment. ^bTime to testosterone recovery-free survival was defined as the time from 1 day after the last dose of relugolix or 4 weeks plus 1 day after the last dose of degarelix to testosterone recovery. Testosterone recovery was defined as testosterone levels back to baseline or more than 280 ng/dL, whichever occurred first. It was censored for patients initiating alternative ADT without recovery at the last testosterone laboratory assessment before the initiation of ADT.