Prostate cancer continues to be one of the most prevalent malignancies affecting men worldwide, with localized cases often requiring a combination of therapeutic approaches to optimize outcomes. The National Comprehensive Cancer Network (NCCN) guidelines suggest that patients with unfavorable localized prostate cancer should undergo a combination of radiation therapy (RT) and androgen deprivation therapy (ADT) (1). ADT paired with conventionally fractionated RT substantially enhances metastases-free and overall survival (2). Emerging data also indicate that adding ADT to ultrahypofractionated RT, or stereotactic body radiation therapy (SBRT), for unfavorable prostate cancer may lower local disease persistence and biochemical recurrence comparable to SBRT alone (3, 4). Despite its effectiveness, ADT in combination with RT continues to be underutilized likely due to concerns over its bothersome side effects and the associated risks of exacerbating cardiovascular comorbidities (5, 6).

In 2020, the FDA granted approval for relugolix, an oral antagonist of gonadotropin-releasing hormone (GnRH) receptors. By directly inhibiting the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), relugolix induces a swift reduction of testosterone levels to significant castration levels (total testosterone 0.7 nmol/L, <20 ng/dl) (7). The phase 3 HERO trial (NCT03085095) compared the effectiveness of this oral GnRH receptor antagonist versus GnRH agonist leuprolide and demonstrated that relugolix outperformed leuprolide in achieving and maintaining castration (total testosterone 1.73 nmol/L, <50 ng/dl) (8). By day 29 of treatment, 95% of patients on relugolix attained profound castrate levels compared to just 57% of those receiving leuprolide (8). Among patients taking relugolix, 96.7% maintained castration after 48 weeks versus 88.8% of patients on leuprolide (8). Notably, there were no statistical differences in rates of hormonal toxicities such as generalized fatigue, hot flashes, and musculoskeletal pain (8).

Neoadjuvant/adjuvant relugolix administered over 6 months has been examined in unfavorable localized prostate cancer when alongside conventionally fractionated RT (79.2 Gy in 44 fractions) (9). This combination resulted in 95% achieving castration and 87% reaching profound castration (9). However, the high incidence of rapid profound castration may influence health-related quality of life, particularly among minority and underserved populations, as these groups have previously been reported to exhibit greater rates of non-adherence to hormonal therapies (10). Furthermore, patient-specific characteristics, such as age or comorbidities, may amplify these effects. We conducted a prospective study to evaluate the influence of neoadjuvant relugolix on health-related quality of life (HRQoL) in intermediate- and high-risk prostate cancer patients prior to starting SBRT.

Our team carried out a prospective study of subjects with unfavorable, localized prostate adenocarcinoma treated at Georgetown University Hospital (IRB 12-1175). As per institutional protocol, patients received a short-term treatment of relugolix for 6 months, along with SBRT. We reviewed patients’ medical records to gather demographic and oncologic information, including age, ethnicity, body mass index (BMI), prostate volume, pretreatment PSA levels, T stage, Gleason score, and treatment dosage. D’Amico criteria were utilized to categorize patient risk groups.

Growing evidence suggests that achieving profound castration (serum testosterone levels of <20 ng/dl) may yield better outcomes in specific clinical contexts, although current guidelines define effective castration as testosterone levels of <50 ng/dl (13). While the impact of testosterone levels of <20 ng/dl on HRQoL remains ambiguous, it is reassuring to note that 87% of our patient cohort achieved profound castration without any clinically meaningful deterioration in HRQoL. This result aligns with findings from the Radiation Therapy Oncology Group (RTOG) 0815 randomized trial, which investigated dose-escalated radiation with or without short-term androgen suppression in intermediate-risk prostate adenocarcinoma (5). In that study, short-term androgen suppression using injectable GnRH receptor agonists combined with oral antiandrogen therapy over a 6-month period demonstrated no effect on EQ-5D VAS scores up to 5 years following radiation therapy. These findings are particularly relevant for intermediate-risk patients considering the addition of relugolix to their SBRT regimen.

Similar to other SBRT cohorts, our patient population was older and presented with moderate reductions in baseline HRQoL before treatment. While androgen deprivation therapy is associated with musculoskeletal pain (30%) and fatigue (25%) (8), we did not see increased difficulties with self-care, usual activities, mobility, or pain/discomfort in patients receiving short-term relugolix. Notably, 41% of our study population was non-white, representing diverse socioeconomic and racial backgrounds (14). The absence of adverse HRQoL impacts in this socially diverse cohort further supports the safety of short-term relugolix use in these patients.

We also conducted a deeper investigation into a subset of eight patients who had “severely” negative effect from ADT defined as those whose EQ VAS score decreased by 20 or greater. An arbitrary cutoff point of 20 was decided because there were recent studies, which suggested more flexible criteria to define the clinical significance in differences as two or three times the conventional MID (0.5 of SD at baseline) (15) or as the standard error of the measure (SEM) represented by S D * 1 − C r o n b a c h ′ s   a l p h a (16).

Interestingly, these eight patients had no significant differences in all of the reported baseline demographic and clinical characteristics compared to the rest of the cohort. Among these eight patients, the majority reported to have “some problems” from “no problem” in baseline in the mobility (n = 4) and usual activities (n = 4) sections ( Table 3 ).

Also, the EQ VAS score decrease did not seem to reflect on the individual items, as three of these eight patients reported to have no change in all five sections and remained as good health state (“11111”), including the patient who reported to have the greatest decrease in the EQ VAS score of 45 points. This could suggest that these five dimensions may not have adequately represent the side effects the patients experienced from the hormonal therapy as represented in the EQ VAS score.

One possible missing component accounting for the observed discrepancy is patient-reported fatigue, a commonly reported bothersome effect of hormonal therapy; our previous study showed that while most patients had significantly increased patient-reported fatigue, they were not impacted in the self-care aspect (17). It is also worth noting that a recent study conducted by our team on the effects of relugolix on patient-reported sexual function found that, while neoadjuvant relugolix was linked to a significant decline in sexual function, the majority of patients did not express concern about this effect (18) Last, the major advantage of relugolix, particularly for patients experiencing significant side effects from hormonal therapy, is that the medication effects can be resolved quickly when stopped (8).

Future studies should focus on comparing it to GnRH agonist-induced change in quality of life. Neoadjuvant relugolix administered before prostate SBRT did not have a clinically meaningful impact on patient-reported health-related quality of life. There were no statistically significant reductions in any of the five individual items comprising EQ-5D-3L. Additional research should be directed toward comparing quality-of-life outcomes for patients on relugolix to those resulting from GnRH agonist treatment.