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Androgen-deprivation therapy (ADT) with an oral gonadotropin-releasing hormone (GnRH) antagonist rapidly suppressed testosterone and cut the incidence of serious heart events compared to an injectable GnRH agonist, a phase III trial found.

The so-called HERO study of over 900 patients met its primary endpoint, demonstrating that castration at 48 weeks was maintained in 96.7% of those assigned to oral relugolix compared to 88.8% of those on leuprolide injection, meeting prespecified criteria for both non-inferiority and superiority (P<0.001), reported Neal Shore, MD, of the Carolina Urologic Research Center in Myrtle Beach, South Carolina.

"Most notably, risk of major adverse cardiovascular events [MACE] was 54% lower in the relugolix group compared with leuprolide," said Shore during his presentation at the American Society of Clinical Oncology (ASCO) virtual meeting. "Relugolix is a novel, oral GnRH antagonist that has the potential to become a new standard for ADT in advanced prostate cancer."

Approximately 30% of men with prostate cancer have known cardiovascular disease, and many more have comorbid risk factors, said Shore, adding that since the 1990s, the proportion of prostate cancer patients dying of cardiovascular disease has surpassed those dying from prostate cancer itself.

In the study, cumulative incidence of MACE at 48 weeks (non-fatal stroke or myocardial infarction, or death from any heart-related cause) was 2.9% with the oral drug versus 6.2% with leuprolide (HR 0.46, 95% CI 0.24-0.88). And among those with a history of serious cardiac events, leuprolide was associated with a substantially higher risk of MACE compared to relugolix (17.8% vs 3.6%, respectively, OR 5.8, 95% CI 1.5-23.3).

Findings from the study were published simultaneously in the .

All key secondary endpoints in the trial significantly favored relugolix. Patients on the oral drug achieved rapid testosterone reductions, with a higher proportion reaching castrate levels (<50 ng per deciliter) at days 4 and 15 versus leuprolide (P<0.001 for both):

• Day 4: 56.0% vs 0%
• Day 15: 98.7% vs 12.0%

In the relugolix arm, 79.4% of patients had a PSA response at day 15, as compared to 19.8% with leuprolide (P<0.001).

Relugolix achieves both luteinizing hormone and follicle-stimulating hormone (FSH) suppression via direct inhibitory effect on pituitary GnRH receptors, Shore explained, and thereby does not result in the early testosterone surge seen with luteinizing hormone-releasing hormone (LHRH) agonists, which can sometimes lead to a flare of symptoms.

At weak 24, FSH suppression was also improved with relugolix (mean 1.72 vs 5.95 IU/L, P<0.0001).

"Even though no level 1 outcome data exist for the superiority of a GnRH antagonist over a GnRH agonist with respect to cardiovascular events or death from cardiovascular causes, the testosterone-suppression data for GnRH antagonists, oral or subcutaneous, are level 1," wrote Celestia Higano, MD, of the Seattle Cancer Care, in an NEJM .

"Therefore, it is likely that the anticancer effects of a GnRH antagonist will not be inferior to those of a GnRH agonist and may be beneficial in terms of cardiovascular events that may be life-limiting," she continued. "Close monitoring will be required because exposure to oral relugolix for longer than 48 weeks has not been studied and many oral agents are associated with adherence problems, especially if they cause adverse effects."

Frequency of all-grade adverse event (AEs) was similar for the two treatments, at 92.9% in the relugolix arm and 93.5% in the leuprolide arm. Diarrhea was reported in a higher proportion of patients on relugolix (12.2% vs 6.8%), though Shore noted that most were low-grade and manageable. Incidence of grade ≥3 AEs was similar as well (18.0% with relugolix and 20.5% with leuprolide), and fatal events were rare (1.1% vs 2.9%, respectively).

For cardiac safety overall, 3.9% experienced an adverse cardiovascular event on relugolix versus 7.1% with leuprolide.

The phase III HERO was an international, open-label study that randomized 930 evaluable patients with locally advanced or metastatic prostate cancer to oral relugolix (n=622) or leuprolide injection (n=308). Relugolix was given daily (360 mg loading dose on day 1 and 120 mg thereafter), while leuprolide was administered as a subcutaneous injection every 3 months (22.5 mg).

Median patient age was 71, with more than two-thirds under age 75. About half of the cohort had biochemical or clinical relapse following their primary treatment, 23% had newly diagnosed metastatic androgen-sensitive disease, and 27% had advanced localized disease and were ineligible for curative approaches. Over 90% of patients had cardiovascular risk factors, with 14% having a history of MACE.

Key inclusion criteria were biochemical or clinical relapse that called for 1 year of ADT, serum testosterone levels of 150 ng/dL or above, a PSA of 2.0 ng/mL or higher, and good performance status. Those with a MACE event within 6 months of trial enrollment were excluded.