medwireNews: Men with advanced prostate cancer who receive the gonadotropin-releasing hormone antagonist relugolix are more likely to have sustained suppression of testosterone than those treated with leuprolide acetate, HERO trial data show.
The phase 3 study, presented at the virtual 2020 ASCO Annual Meeting and simultaneously published in The New England Journal of Medicine, also found that relugolix was associated with a significantly lower risk for major adverse cardiovascular events (MACE) than leuprolide.
For the trial, men with either biochemical or clinical relapse after local primary intervention with curative intent, newly diagnosed hormone-sensitive metastatic disease, or advanced localized disease unlikely to be cured by local primary intervention with curative intent were randomly assigned to receive relugolix (120 mg/day orally; n=622) or the luteinizing hormone-releasing hormone agonist leuprolide (22.5 or 11.25 mg every 3 months by injection; n=308) for 48 weeks.
In all, 96.7% of men in the relugolix group had sustained testosterone suppression below castrate levels (<50 ng/dL) from day 29 until week 48.
By comparison, the sustained castration rate was 88.8% in the leuprolide group.
Statistical analysis showed that with a difference of 7.9 percentage points relugolix was noninferior, and indeed superior, to leuprolide for this primary endpoint.
Furthermore, relugolix was superior to leuprolide for a number of key secondary endpoints, including the cumulative probability of castration on day 4 (56.0 vs 0.0%) and day 15 (98.7 vs 12.0%), testosterone suppression to profound castrate levels (<20 ng/dL) on day 15 (78.4 vs 1.0%), and a confirmed prostate-specific antigen response at day 15 (79.4 vs 19.8%).
Neal Shore (Carolina Urologic Research Center, Myrtle Beach, South Carolina, USA) and co-investigators also note that testosterone suppression to castrate levels was rapid in the relugolix group, reaching a mean of 38 ng/dL by day 4, which was then maintained throughout the treatment period.
Conversely, the mean testosterone level in the leuprolide group initially increased, to 625 ng/dL on day 4, before decreasing to castrate levels from day 29 onwards.
Shore and co-authors say this shows that “[n]ot only does treatment with relugolix avoid the risks of a surge in testosterone and the need for an antiandrogen to prevent the flare of symptoms, but the rapid suppression of testosterone may also be beneficial for clinicians and patients when considering additional antineoplastic interventions such as radiation or chemotherapy.”
Testosterone recovery was also greater with relugolix than with leuprolide. At 90 days after treatment discontinuation, mean levels were 288.4 ng/dL and 58.6 ng/dL, respectively, in a subgroup of 184 patients with extended follow-up.
The researchers also found that a similar proportion of patients in each group experienced an adverse event, most commonly hot flash (54.3% with relugolix and 51.6% with leuprolide).
More patients receiving relugolix versus leuprolide experienced any grade diarrhea (12.2 vs 6.8%) but fewer experienced MACE (2.9 vs 6.2%).
Indeed, the risk for MACE was a significant 54% lower with relugolix than with leuprolide, and the data suggest that “that this difference may have been even greater in patients with preexisting cardiovascular risk factors,” Shore et al remark.
In these patients, the incidence of MACE was 3.6% (three of 84 patients) in the relugolix compared with 17.8% (eight of 45 patients) in the leuprolide group.
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2020 ASCO Annual Meeting; 29–31 May
N Engl J Med 2020; doi:10.1056/NEJMoa2004325