Oral relugolix given daily is superior to standard androgen-deprivation therapy (ADT) with leuprolide (Lupron) in men with advanced prostate cancer, according to the results of the phase 3 HERO study, which were reported at the ASCO 2020 virtual annual meeting and published online before the meeting (Shore ND, et al. N Engl J Med. 2020;382:2187-2196).
Almost all (96.7%) the men who received ADT with relugolix maintained castrate levels of testosterone through 48 weeks (the primary end point) versus 88% of men who received ADT with leuprolide (P <.001 for superiority). Of note, major cardiac events were cut by 54% with relugolix treatment.
In June 2020, the FDA granted a priority review for relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, for the treatment of advanced prostate cancer.
ADT with leuprolide acetate, a luteinizing hormone-releasing hormone agonist, is administered as an injection and is associated with increased risk for major cardiac events, including myocardial infarction, sudden cardiac death, and stroke; the new oral GnRH therapy reduces the risk for those events substantially.
Approximately 30% of men with prostate cancer have cardiovascular disease, and 90% of those enrolled in the HERO study had cardiac risk factors.
“In the HERO trial, the oral GnRH antagonist relugolix showed sustained testosterone suppression superior to that of leuprolide and resulted in a 54% lower risk of major cardiovascular events than with leuprolide,” stated lead investigator Neal D. Shore, MD, FACS, Director, Carolina Urologic Research Center, Myrtle Beach, SC.
“Relugolix is a novel oral GnRH antagonist that has the potential to become a new standard for ADT in advanced prostate cancer.”
The global phase 3 HERO trial randomized 930 men with advanced prostate cancer in a 2:1 ratio to oral relugolix 120 mg daily (N = 622) or to leuprolide injections (N = 308) every 3 months for a total of 48 weeks. Eligible patients had either evidence of biochemical or clinical relapse after primary therapy with curative intent, newly diagnosed hormone-sensitive metastatic disease, or advanced localized disease that is unlikely to be cured. Patients who had major cardiac events within 6 months of enrollment were excluded.
At baseline, approximately 31% of the patients (median age, 71 years) had metastatic disease, 43% had a Gleason score of 8 to 10, 11.9% had previous ADT, and 30.3% had previous radiotherapy. The median prostate-specific antigen (PSA) level at baseline was 10.8 ng/mL, and the mean testosterone level at baseline was 427.5 ng/dL. The median time to follow-up, including safety, was 52 weeks.
Relugolix met the primary end point of the trial and was superior to leuprolide for all key secondary end points (P <.001). The percentage of patients with a confirmed PSA response at day 15 was 79.4% with relugolix versus 19.8% with leuprolide (P <.001).
Men who received treatment with relugolix achieved castrate levels of testosterone more rapidly than the patients who received leuprolide, and these levels were maintained throughout treatment.
The overall incidence of adverse events was consistent across the 2 treatment arms. Hot flash was the most common adverse event in both arms, at 54.3% for relugolix and 51.6% for leuprolide. Mild or moderate diarrhea was reported in more patients in the relugolix group than in the leuprolide cohort (12.2% vs 6.8%, respectively). There were no treatment withdrawals because of diarrhea.
The mortality rate was 1.1% in the relugolix group and 2.9% in the leuprolide group.
In a prespecified analysis of patients who received 48 weeks of treatment, the incidence of major cardiac events was 2.9% in the relugolix group compared with 6.2% in the leuprolide group, which was 54% lower than with the oral ADT. An even more striking advantage of treatment with relugolix was seen in patients with a reported history of major cardiac events; the incidence of major cardiac events during treatment was 3.6% for relugolix and 17.8% for leuprolide.
“The odds were 4.8 times higher with leuprolide as with relugolix in men with a history of MACE [major cardiac events],” Dr Shore stated.
David R. Wise, MD, PhD, Attending Physician, Genitourinary Medical Oncology, Perlmutter Cancer Center, NYU Langone Health, New York, who discussed this study, called oral ADT a new standard of care.
“Is this practice-changing? Yes, for a subset of patients with a history of significant cardiovascular disease and without gastrointestinal malabsorption problems. I will use this drug to avoid injection-site reactions commonly experienced with degarelix,” Dr Wise emphasized. Degarelix is another injectable GnRH receptor antagonist.
“The concern for noncompliance with an oral drug will necessitate more frequent serum testosterone checks, particularly for monotherapy,” he concluded.
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