Will the FDA approve an oral LHRH antagonist for treatment of prostate cancer?

According to a media release issued yesterday, Myovant Sciences (based in Basel, Switzerland) has submitted a New Drug Application (NDA) for approval of its oral LHRH antagonist, relugolix, in the treatment of men with advanced prostate cancer. If the FDA decides to approve relugolix for this indication, it would be the first oral form of LHRH antagonist available for the treatment of prostate cancer.

Relugolix has been studied in several clinical trials to date, most recently in a randomized, double-blind trial known as the HERO trial. This trial was designed to enroll 1,100 men with advanced prostate cancer (including 430 men with evidently metastatic prostate cancer) who were to be randomized to treatment for 48 weeks with either

  • Relugolix 120 mg tablet administered orally once daily following an oral loading dose of 360 mg on Day 1 or
  • Leuprolide acetate 22.5 mg (or 11.25 mg in some Asian countries)

The patients were to be randomized 2:1 to relugolix or leuprolide acetate.

The primary study endpoint was a sustained castration rate defined as the cumulative probability of testosterone suppression to ≤ 50 ng/dL (1.7 nmol/L) while on study treatment from Week 5 through Week 48.

According to the company’s media release:

  • 96.7 percent of men achieved sustained testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks.
  • Relugolix demonstrated superiority to leuprolide acetate based on several secondary endpoints, including
    • Sustained testosterone suppression to castrate levels through 48 weeks
    • Rapid suppression of testosterone at Day 4 and at Day 15
    • Profound suppression of testosterone (< 20 ng/dL) at Day 15
    • Rapid suppression of PSA at Day 15
    • Suppression of follicle-stimulating hormone (FSH) at Week 24
  • The overall incidence of adverse events in the relugolix and leuprolide acetate groups was comparable (92.9 vs. 93.5 percent, respectively).
  • Major adverse cardiovascular events were reported in 2.9 percent of men in the relugolix group versus 6.2 percent of men in the leuprolide acetate group.
  • The major adverse cardiovascular events included non-fatal myocardial infarction, non-fatal stroke, and all-cause mortality.

According to Myovant Sciences, data from Phase II clinical trials in men with prostate cancer had previously shown that:

  • “Upon treatment discontinuation of relugolix, testosterone levels rose above castrate levels within days.”

It is clear that the HERO study is ongoing, so what is not entirely clear at this time is the number of patients for whom the primary and secondary endpoints have already been met and whose data are therefore being used to support this NDA.

The availability of an oral form of LHRH antagonist would present men with advanced and high-risk forms of prostate cancer with major new opportunities for many reasons:

  • It would be easy to stop therapy quickly if side effects proved to be either dangerous to the patient or simply unmanageable (in the case of those men for whom hot flashes are so frequent and/or severe as to be unbearable).
  • It might prove possible to stop therapy  in order to regain sexual function quickly (although data to support such behavior would need to show that this was both safe and “fast enough”)
  • It might facilitate the use of intermittent androgen deprivation therapy in the treatment of advanced forms of prostate cancer. We wonder, for example, whether it might be possible (for at least some appropriately selected patients) to “cycle” on and off a drug like relugolix, i.e., take the drug every day for 4 weeks and then come off it for 2 weeks before starting the cycle again.
  • It would allow patients to avoid the need for regular injections of standard formulations of other LHRH agonists and antagonists.

We should note that relugolix is also being developed for the treatment of other disorders treated with older LHRH agonists (such as endometriosis and uterine fibroids).

2 Responses

  1. AnCan has been in discussion with Myovant for several months about how they can make a “splash entry” in the US market. We have suggested various support opportunities targeted at men on LHRH drugs.

    We also found it strange that they set the clinical trial up against an agonist rather than the antagonist they are offering. Len Sierra also pointed out that the threshold for testosterone suppression was high in today’s clinical environement at <50 mg versus <30 mg.

    Nonetheless, we agree with your observations that an oral LHRH drug would be a boon to many men. Interestingly, AbbVie makes an oral LHRH approved for endometriosis called Orilissa – it does not appear to be offered even off-label for PCa.

  2. Rick:

    I’d make a bet with you that it wad the FDA who asked them to do the trial against leuprolide actetate for the simple reason that it is the single most widely used (and therefore “standard”) form of ADT used here in the USA and most of the rest of the world. Whether we like it or not < 50 ng/dl is still the established testosterone level considered to define "castrate". You will notice, however, that Myovant has provided data indicating that their drug lowered serum T levels much more than the leuprolide acetate did.

    Thanks for the info about the Myovant offices. Their formal HQ is actually in Basel, Switzerland.

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