Relugolix May Replace Current Standard of Care for T-Suppression in Advanced Prostate Cancer

Neal D. Shore, FACS, MD

Findings from the phase 3 HERO trial show continued superiority of relugolix (Relumina) compared with leuprolide (Lupron) in patients with advanced prostate cancer. In a presentation during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, testosterone (T)-suppression was sustained through 48 weeks with relugolix, and there was also fast T-recovery after discontinuation, and a 50% reduction in major adverse cardiovascular events (MACE).¹

Additionally, relugolix achieved castration as early as day 4, suggesting the potential for this agent to become a new standard for T-suppression in this patient population.

“Relugolix is a novel, oral GnRH receptor antagonist that achieves both LH and FSH suppression to its direct inhibitory effect on the pituitary GnRH receptors,” Neal D. Shore, FACS, MD, medical director for the Carolina Urologic Research Center, said in a press release. “This direct inhibition does not result in a testosterone surge.”

The 48-week, global, pivotal phase III trial, which also published in The New England Journal of Medicine, randomized 934 patients with androgen-sensitive advanced prostate cancer in a 2:1 fashion to receive either 120 mg of relugolix orally once daily after a one-time 360 mg loading dose or a 3-month depot injection of leuprolide acetate.² Testosterone recovery was also evaluated in a subset of 184 patients.

The primary end point of the study was to achieve and maintain serum T-suppression to castrate levels (< 50 ng/dL) through 48 weeks. Key secondary endpoints included castration rates at day 4 and day 15, profound castration (< 20 ng/dL) rates at days 4 and 15, PSA response rate at day 15, and FSH levels at week 24.

In order to be included in the study, patients had to have confirmed advanced prostate cancer, ≥1 years of androgen deprivation therapy (ADT), a serum PSA > 2.0 ng/mL, and an ECOG score of 0 or 1. Patients who were expecting to under chemotherapy or surgical therapy within 2 months of initiating ADT, had previous ADT for >18 months for previous systemic cytotoxic therapy for prostate cancer, had active liver disease, or severe cardiovascular risk conditions were excluded from the study.

Of the 624 patients randomized to the relugolix arm, 563 (90.2%) completed treatment compared to 276 of the 310 (89.0%) who were given leuprolide. Moreover, 59 of the 624 (9.5%) and 32 of the 310 (10.3%), respectively, terminated their treatment early. The remaining patients were randomized, but not treated.

The characteristics of the patients at baseline were well balanced between the 2 treatment groups. Moreover, 50.2% of the men enrolled had biochemical recurrence after definitive treatment for prostate cancer, 28.9% were enrolled in North America, and 11.5% were from Japan. More than 90% of the patients also had at least 1 cardiovascular risk factor.

Overall, 96.7% (95% CI, 94.9%-97.9%) of men treated with relugolix achieved and maintained castration through 48 weeks compared to 88.8% on leuprolide. Notably, the difference of 7.9% (95% CI, 4.1%-11.8%) demonstrated noninferiority (margin -10%) and superiority (P < 0.0001) of relugolix to leuprolide. All key secondary endpoints tested also demonstrated superiority over leuprolide (P < 0.0001).

In the subset of patients evaluated for testosterone recovery, median T-levels were 270.76 ng/dL in the relugolix group compared to 12.26 ng/dL in the leuprolide group 90 days after discontinuation of therapy.

In a prespecified analysis, the incidence of MACE was found to be lower in the relugolix group than in the leuprolide group (2.9% vs 6.2%, respectively). Otherwise, the safety and tolerability profiles of the 2 agents were generally similar. Adverse events (AEs) reported for >10% of patients treated with relugolix or leuprolide were hot flush (54.3% vs 51.6%, respectively), fatigue (21.5% vs 18.5%), constipation (12.2% vs 9.7%), diarrhea (12.2% vs 6.8%), arthralgia (12.1% vs 9.1%), and hypertension (7.9% vs 11.7%). Notably, AEs of diarrhea were of grade 1 or 2 and did not result in study discontinuation.

“Relugolix once daily was well tolerated with an adverse event profile consistent with T-suppression,” Shore said. “Most notably, the risk of major adverse cardiovascular events was 54% lower in the relugolix group compared to leuprolide.”

Furthermore, though oral treatments are now commonly used for men with advanced and castration-resistant prostate cancer, concerns remain about adherence to oral ther-apies. However, the investigators indicated that treatment adherence with oral relugolix was more than 99% and similar to that seen with injectable leuprolide.

“Relugolix is a novel, oral GnRH antagonist that has the potential to become a new standard for ADT in advanced prostate cancer,” Shore concluded.

_References:

_{1. Shore ND, George DJ, Saad F, et al. HERO phase III trial: Results comparing relugolix, an oral GnRH receptor antagonist versus leuprolide acetate for advanced prostate cancer. Presented at: 2020 ASCO Virtual Scientific Program. Abstract 5602.}

_{2. Shore ND, Saad F, Cookson MS, et al. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med. doi:10.1056/NEJMoa2004325}

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