A phase 3 randomized controlled trial compared the oral gonadotropin-releasing hormone (GnRH) receptor antagonist relugolix to the injectable GnRH agonist leuprolide for androgen deprivation therapy (ADT) in men with advanced prostate cancer. The HERO study, funded by Myovant Sciences GmbH, was conducted globally and published in the European Urology journal in September 2023. Its primary purpose was to evaluate the impact of relugolix versus leuprolide on health-related quality of life (HRQOL) in patients with advanced prostate cancer during both the treatment phase and testosterone recovery period.
The study included 930 men with advanced prostate cancer who were randomized 2:1 to receive either oral relugolix 120 mg daily or leuprolide 3-month depot injections for 48 weeks. Eligible patients were 18 years or older with histologically or cytologically confirmed prostate adenocarcinoma and were candidates for at least 12 months of ADT. Patients could have one of three clinical presentations: biochemical or clinical relapse after local primary intervention, newly diagnosed hormone-sensitive metastatic disease, or advanced localized disease unlikely to be cured by local primary intervention.
The study population had a median age of 71-72 years, with approximately 71% of patients under 75 years old. About 32% had metastatic disease at baseline. The most common clinical presentation was evidence of biochemical or clinical relapse following local primary intervention (around 50% of patients). Baseline characteristics were generally well-balanced between the two treatment groups.
HRQOL was assessed using validated questionnaires - the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and the Prostate Cancer Module (QLQ-PR25). Patients completed these at baseline and multiple time points during treatment and follow-up. The primary HRQOL analysis compared changes from baseline to end of treatment (EOT) at 48 weeks between the relugolix and leuprolide groups.
The key finding was that there were no statistically significant differences between relugolix and leuprolide in changes from baseline to EOT for any of the QLQ-C30 or QLQ-PR25 domains. Both groups showed declines in various functioning domains (role, cognitive, physical, social) and global health status, as well as increases in some symptom domains (fatigue, insomnia, dyspnea) over the 48-week treatment period. However, these changes were generally not considered clinically significant based on established minimally important difference thresholds.
In the testosterone recovery phase, which included a subset of 184 patients followed for 90 days after EOT, the relugolix group reported significantly lower hormonal treatment-related symptoms compared to leuprolide. This suggests a lower burden of hormone-related side effects with relugolix as testosterone levels recover more rapidly after treatment cessation. The relugolix group also showed a significant increase in sexual activity scores during this phase, though sexual functioning scores were similar between groups.
A post-hoc analysis was conducted to identify predictors of HRQOL changes. Baseline domain scores were found to be the strongest predictor across most domains. Patients with high functioning scores or low symptom scores at baseline were at highest risk of experiencing declines in respective domains by EOT. Conversely, those with pre-existing HRQOL impairments at baseline were less likely to experience further declines.
The study had several limitations. The open-label design may have introduced bias in patient-reported outcomes. The testosterone recovery phase included a relatively small subset of patients that was not balanced between treatment groups. The QLQ-C30 and QLQ-PR25 instruments, while validated, may not comprehensively capture all relevant ADT-related symptoms. Additionally, the 48-week treatment duration may not reflect longer-term HRQOL impacts of these therapies.
The authors concluded that oral relugolix provides similar patient-reported HRQOL to injectable leuprolide during ADT for advanced prostate cancer. The potential advantages of relugolix include more rapid testosterone suppression, lower risk of major adverse cardiovascular events (shown in previous analyses), and faster testosterone recovery after treatment cessation. The latter may translate to a lower burden of hormonal symptoms during the recovery period.
These findings have several potential clinical implications. First, they provide reassurance that switching from injectable to oral ADT is unlikely to negatively impact patients' quality of life. The similar HRQOL profiles, combined with the convenience of oral administration, may make relugolix an attractive option for many patients. The faster testosterone recovery with relugolix could be particularly beneficial for patients undergoing intermittent ADT or those wishing to regain sexual function more quickly after treatment.
The study also highlights the importance of baseline HRQOL status in predicting treatment impact. Clinicians may want to pay particular attention to patients with high baseline functioning, as they may be more likely to experience noticeable declines. Conversely, patients already experiencing HRQOL impairments may be less likely to deteriorate further.
It's worth noting that while HRQOL was similar between treatments, previous analyses of the HERO trial showed superior sustained testosterone suppression and a lower risk of major adverse cardiovascular events with relugolix. These factors, along with the HRQOL findings, should be considered in treatment decision-making.
The results also underscore the general impact of ADT on various aspects of HRQOL, regardless of the specific agent used. Clinicians should be prepared to discuss and manage potential declines in physical, cognitive, and social functioning, as well as increases in fatigue and other symptoms. Supportive care strategies to maintain HRQOL during ADT remain important.
Future research directions suggested by this study include longer-term HRQOL assessments, more comprehensive evaluation of sexual function recovery, and studies combining relugolix with other agents used in advanced prostate cancer management. Additionally, real-world studies could help confirm these findings and identify any HRQOL differences that may emerge with longer-term use.
In conclusion, this large phase 3 trial provides important data on the HRQOL impact of a novel oral ADT option compared to standard injectable therapy. The findings support relugolix as a therapeutic alternative with similar HRQOL effects to leuprolide, while offering potential advantages in terms of administration route and physiological effects. As ADT remains a cornerstone of advanced prostate cancer management, these results will help inform treatment choices and patient counseling in clinical practice.
References
Tombal B, Collins S, Morgans AK, et al. Impact of Relugolix Versus Leuprolide on the Quality of Life of Men with Advanced Prostate Cancer: Results from the Phase 3 HERO Study. Eur Urol. 2023;84(6):579-587. doi:10.1016/j.eururo.2023.09.007
