THE "NEW" PROSTATE CANCER INFOLINK

The results of the Phase III HERO trial of relugolix — the first oral LHRH antagonist for treatment of advanced prostate cancer — have now been reported in the New England Journal of Medicine (NEJM) and at the “virtual” annual meeting of the American Society for Clinical Oncology (ASCO). We had previously commented on the potential of this new product (although it still has to be approved for use by any regulatory agency, e.g., the US Food and Drug Administration).

According to the article by Shore et al. in the NEJM, 930 patients with advanced prostate cancer were randomly assigned to treatment with either relugolix (120 mg orally once daily) or leuprolide acetate (injections every 3 months) for 48 weeks in a 2:1 ratio (i.e., 622 patients were treated with relugolix and 308 were treated with leuprolide acetate injections). Additional information is also available in a report on the MedPage Today web site.

The primary end point was testosterone suppression to castrate levels (<50 ng/dl), sustained over the 48-week follow-up period, and there were several., additional secondary end points.

Here are the core study findings:

• Sustained, castrate levels of serum testosterone at 48 weeks were observed in
  • 96.7 percent of men treated with relugolix
  • 88.8 percent of men treated with leuprolide acetate
  • This result was statistically superior in favor of relugolix (P < 0.001)
• Castrate levels of serum testosterone at Day 4 after initiation of therapy were observed in
  • 56 percent of men treated with relugolix
  • No men treated with leuprolide acetate
  • This result was statistically significant in favor of relugolix (P < 0.001)
• Castrate levels of serum testosterone at Day 15 after initiation of therapy were observed in
  • 98.7 percent of men treated with relugolix
  • 12.0 percent of men treated with leuprolide acetate
  • This result was statistically significant in favor of relugolix (P < 0.001)
• A PSA response was evident at Day 15 after initiation of treatment among
  • 79.4 percent of patients treated with relugolix
  • 19.8 percent of patients treated with leuprolide acetate
  • This result was statistically significant in favor of relugolix (P < 0.001)
• The incidence of major cardiovascular effects was
  • 2.9 percent among men treated with relugolix
  • 6.2 percent among men treated with leuprolide acetate
  • Hazard ratio (HR) = 0.46
• Frequency of all-grade adverse event (AEs) was similar for the two treatments:
  • 92.9 percent among patients treated with relugolix
  • 93.5 percent among patients treated with leuprolide acetate
• Diarrhea was more common among patients treated with relugolix (12.2 percent) as compared to men treated with leuprolide acetate (6.8 percent), but was generally of low-grade and manageable.
• Fatal adverse events were rare, but again favored relugolix
  • 1.1 percent among men treated with relugolix
  • 2.9 percent among men treated with leuprolide acetate
• In a subgroup of 184 patients followed for testosterone recovery, the average (mean) testosterone levels 90 days after treatment discontinuation were
  • 288.4 ng/dl in the patients treated with relugolix
  • 58.6 ng/dl in the patients treated with leuprolide acetate

In their article in the NEJM, Shore et al conclude that:

In this trial involving men with advanced prostate cancer, relugolix achieved rapid, sustained suppression of testosterone levels that was superior to that with leuprolide, with a 54% lower risk of major adverse cardiovascular events.

An editorial by Higano also appears in the NEJM for those who have full access to that publication.

Relugolix has been developed by Myovant Sciences, and the HERO trial was sponsored by that company. The following appear (to Prostate Cancer International) to be the most likely issues related to the real world use of this product:

• The US FDA seems likely to approve the prescription of this product relatively soon (and probably before the end of 2020).
• The price of the product relative to the price of the available, injectable LHRH agonists and antagonists will be a critical factor in determining uptake of this product.
• Here in the US, patient co-pays (for an oral product as opposed to the injectable products) will also impact uptake.
• Real world compliance with an oral drug may be an issue (and compliance with injections every 3, 4, or 6 months may be a lot easier for some patients).
• For any patient with advanced prostate cancer and a history of heart disease, there may well be a very real and important reduction in risk of cardiovascular complications and deaths from treatment with relugolix.

All other things being equal, it would seem to Prostate Cancer International that this oral LHRH antagonist would (on the basis of these data) be an excellent option for a very high proportion of men who need first line androgen deprivation therapy (ADT), once it gets approval. However, as noted by Higano in her editorial, patients have only been followed on this drug for 48 weeks at most. It will be important to monitor longer-term use with care — just in case there are additional, significant side effects that may only come to light in the future.

Filed under: Drugs in development, Living with Prostate Cancer, Management, Treatment | Tagged: antagonist, antiandrogen, HERO, LHRH, oral, relugolix, trial |