Relugolix Does Not Improve Castration Resistance-Free Survival in Advanced Prostate Cancer

Fred Saad, MD, FRCS

In the phase 3 HERO trial of relugolix (Orgovyx) versus standard of care leuprolide (Lupron) in men with advanced prostate cancer, relugolix failed to significantly delay onset of castration resistance, according to a presentation given during the American Urological Association 2021 Annual Meeting.¹

At 48 weeks, the castration resistance–free survival (CRFS) rate was 74.3% (95% CI, 68.6%-79.2%) with relugolix vs 75.3% (95% CI, 66.7%-81.9%) with leuprolide in the metastatic disease cohort (n = 434; HR, 1.03; 95% CI, 0.68-1.57; P = .84). Similar CRFS rates were observed in the overall modified intention-to-treat population (mITT; n = 1074).

A post-hoc, stepwise, multivariate Cox regression analysis showed that the baseline characteristics of prostate-specific antigen (PSA) of 20 or higher (P < .0001), baseline metastatic disease (P < .0001), and former or current smoker (P = .0284) were associated with a CRFS event.

Additionally, all patients were under the castration threshold of less than 50 ng/dL at the time of their CRFS event except for 2 treated with leuprolide who died without attaining castration.

“Results suggest that low testosterone levels on [androgen deprivation therapy] ADT are not a driver of early castration resistance,” said lead study author Fred Saad, MD, FRCS, professor and chairman of urology, director of Genitourinary Oncology, the Raymond Garneau Chair in Prostate Cancer Research, director of clinical research, and director of the Molecular Oncology Research Laboratory in Prostate Cancer, at the University of Montreal Hospital Center, during a virtual presentation of the data.

ADT, consisting of gonadotropin-releasing hormone (GnRH) agonists or antagonists, remains the cornerstone of treatment for patients with prostate cancer, Saad explained.

Relugolix is a first-in-class, oral, highly selective GnRH receptor antagonist that was approved by the FDA in December 2020 for use in adult patients with advanced prostate cancer.² The approval was based on initial findings from the HERO trial, in which 96.7% of patients treated with relugolix had suppression of testosterone to castrate levels vs 88.8% with leuprolide.³ Relugolix was also associated with a 54% lower risk of major adverse cardiovascular effects compared with leuprolide.^1,3

This analysis of the HERO trial sought to further characterize the efficacy profile of relugolix in the context of CRFS, a clinically relevant indicator of disease progression and a prespecified secondary end point, in the mITT population and the metastatic disease population.

Patients enrolled on the HERO trial were randomized 2:1 to receive 120 mg of oral relugolix once daily after a single loading dose of 360 mg, or leuprolide injections every 12 weeks for 48 weeks.

Patients were stratified by geographic region, the presence or absence of metastatic disease, and age.

CRFS was defined as the time from the date of the first dose of treatment to the date of confirmed PSA progression per the Prostate Cancer Clinical Trials Working Group 3 criteria while castrated or death from any reason, whichever occurred earlier.

In the mITT population, 717 patients received relugolix and 357 received leuprolide. In the metastatic cohort, 290 patients received relugolix vs 144 who received leuprolide.

Baseline patient and clinical characteristics were similar between the mITT and metastatic disease populations.

Overall, most patients were aged 75 years or younger with a median age of 71 years. Most patients were European. Additionally, most patients had bone only metastasis at the time of study entry vs lymph node only, visceral only, or multiple sites of metastasis.

In the mITT population, testosterone values at the time of CRFS events with relugolix were 0 ng/dL to 10 or less ng/dL (n = 33), 10 ng/dL to 20 or less ng/dL (n = 43), 20 ng/dL to 30 or less ng/dL (n = 7; plus 1 death), 30 ng/dL to 40 or less ng/dL (n = 1), 40 ng/dL to 50 or less ng/dL (n = 3), or above 50 ng/dL (n = 0). In the leuprolide group, testosterone values were 0 ng/dL to 10 or less ng/dL (n = 22; plus 4 deaths), 10 ng/dL to 20 or less ng/dL (n = 13; plus 1 death), and above 50 (2 deaths).

Last testosterone values after CRFS events during treatment with relugolix were 0 ng/dL to 10 or less ng/dL (n = 36), 10 ng/dL to 20 or less ng/dL (n = 39), 20 ng/dL to 30 or less ng/dL (n = 7), 30 ng/dL to 40 or less ng/dL (n = 1), 40 ng/dL to 50 or less ng/dL (n = 1), or above 50 ng/dL (n = 4). In the leuprolide group, testosterone values were 0 ng/dL to 10 or less ng/dL (n = 27), 10 ng/dL to 20 or less ng/dL (n = 11), 20 ng/dL to 30 or less ng/dL (n = 1), and above 50 (n = 3).

Regarding safety, the frequencies of adverse effects (AEs) were similar for relugolix vs leuprolide in the metastatic disease cohort, and no new safety signals were observed.

In the metastatic disease cohort, 94.2% of men treated with relugolix and 89.6% of men treated with leuprolide experienced at least 1 AE.

The AEs reported in at least 5% of patients treated with relugolix included hot flush (n = 146; 50.3%), fatigue (n = 67; 23.1%), arthralgia (n = 47; 16.2%), constipation (n = 45; 15.5%), hypertension (n = 34; 11.7%), nausea (n = 32; 11.0%), diarrhea (n = 29; 10.0%), back pain (n = 28; 9.7%), weight gain (n = 26; 9.0%), nasopharyngitis (n = 24; 8.3%), peripheral edema (n = 23; 7.9%), asthenia (n = 21; 7.2%), musculoskeletal pain (n = 21; 7.2%), insomnia (n = 20; 6.9%) , urinary tract infection (n = 20; 6.9%), extremity pain (n = 19; 6.6%), increased alanine aminotransferase (ALT; n = 18; 6.2%), and urinary incontinence (n = 18; 6.2%).

The AEs reported in at least 5% of patients treated with leuprolide included hot flush (n = 66; 45.8%), fatigue (n = 29; 20.1%), arthralgia (n = 13; 9.0%), constipation (n = 22; 15.3%), hypertension (n = 14; 9.7%), nausea (n = 10; 6.9%), diarrhea (n = 7; 4.9%), back pain (n = 22; 15.3%), weight gain (n = 13; 9.0%), nasopharyngitis (n = 5; 3.5%), peripheral edema (n = 13; 9.0%), asthenia (n = 10; 6.9%), musculoskeletal pain (n = 8; 5.6%), insomnia (n = 11; 7.6%) , urinary tract infection (n = 6; 4.2%), extremity pain (n = 10; 6.9%), increased ALT (n = 4; 2.8%), and urinary incontinence (n = 8; 5.6%).

_References

_{1. Saad F, George DJ, Cookson MS, et al. Relugolix vs leuprolide effects on castration resistance-free survival from the phase 3 HERO study in men with advanced prostate cancer. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract MP24-07.}

_{2. FDA approves relugolix for advanced prostate cancer. News release. FDA. December 18, 2020. Accessed September 11, 2021. https://bit.ly/3z4UCQP}

_{3. Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med. 2020;382(23):2187-2196. doi:10.1056/NEJMoa2004325}