by Reynald Castaneda in London.

Myovant Sciences’ Phase III relugolix trial in castrate-sensitive prostate cancer reporting of a positive trend in reducing major cardiovascular (CV) issues drew mostly expert scepticism. The trial was not powered to demonstrate this advantage and mechanism blanks on how relugolix was able to do so persist, they said.

On 1 June, Myovant’s share price skyrocketed 55% after data from its Phase III HERO trial (NCT03085095) comparing relugolix with generic leuprolide were presented at the recent American Society of Clinical Oncology (ASCO) Virtual Meeting (29–31 May). Myovant’s market cap is $1.54bn.

While experts acknowledged relugolix’s CV event reduction trend is in line with existing data in other gonadotropin-releasing hormone (GnRH) antagonists, most noted that even taken in totality, analyses thus far are only hypothesis-generating.

Myovant submitted a New Drug Application to the FDA in April, following topline HERO results in November 2019. Although HERO data are approvable, it will have significant uptake hurdles considering relugolix will likely have a hefty copay in contrast with leuprolide, experts said, with one noting it could be as much as 20% of the list price. It may also be easier to have new patients start on once-daily, oral relugolix rather than switching those used to leuprolide’s injection administration of once every three months, they said. While one expert noted that relugolix would be a boon for localised disease patients, others argued more data are needed.

Myovant did not respond to a comment request.

Relugolix trial: reduced CV event data come with caveats

Relugolix showed a lower CV event incidence in HERO than leuprolide, said Dr Benjamin Maughan, assistant professor, Genitourinary Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City. Adverse CV events were observed in 3.9% of 662 relugolix-treated patients versus 7.1% in 308 leuprolide patients (Abstract no. 5602). Specifically, 2.4% of relugolix patients had ischemic heart disease, versus 1.6% with leuprolide. Some 2.9% and 6.2% of patients in the relugolix and leuprolide arms, respectively, had a major adverse CV event (MACE).

In the US, with increasing metabolic disease rates, a significant number of patients would be ideal for relugolix, Maughan said. In a population-based study of CVD mortality risk in US cancer patients, a majority of deaths include those in prostate cancer patients (Sturgeon, KM, et. al, Eur Heart J. 2019 Dec 21;40(48):3889-3897). One theory is that reduction of androgen such as testosterone leads to lean muscle mass loss and then fatigue, which paves the way for the patient being less active, explained Dr Walter Stadler, director, Genitourinary Oncology Program, University of Chicago, Illinois.

HERO data paint a consistent picture that GnRH antagonists could potentially reduce CV event risk, Maughan said. In a pooled data analysis of six Phase III trials among men with pre-existing CVD, risk of CV events within one year of initiating therapy was lower in those taking GnRH antagonists versus GnRH agonists (p=0.002; Albertsen, P, et. al, Eur Urol, 2014 Mar;65(3):565-73).

However, HERO was not powered to make a distinction between relugolix and leuprolide in terms of impact on CV issues, said Dr Robert Diecer, section head, medical oncology, University of Virginia School of Medicine, Charlottesville. CV event reduction is not listed as an endpoint on the page for the 1,100-patient trial, and details from ASCO did not note the p-value.

The aforementioned pooled data supporting GnRH antagonists are also only hypothesis-generating, noted Dr Bobby Shayegan, director, McMaster Institute of Urology, McMaster University, Hamilton, Canada. The definitive answer will come from Saint-Prex, Switzerland-headquartered Ferring Pharmaceuticals’ Phase III PRONOUNCE trial (NCT02663908) comparing its GnRH antagonist Firmagon (degarelix) with leuprolide, as the trial’s primary endpoint is MACE reduction, Shayegan said. Oral relugolix is more attractive than Firmagon considering the latter’s inconvenient once-a-month injection and painful injection-site reaction, noted Shayegan. Firmagon was approved in the US in December 2008.

Still, HERO shows a trend supporting the principle that relugolix reduces CV event risk versus leuprolide, Maughan said. In HERO’s MACE graph, leuprolide has a notable uptick in cumulative CV event incidence over the first 12 weeks, which then slows down to the extent that both relugolix and leuprolide curves increase in parallel, Stadler said. One possible cause of the leuprolide uptick is that there is a testosterone flare experienced with this drug in the first few weeks, but more information is needed, he noted.

But Shayegan disagreed with the link between testosterone and CV event risk, because MACE continued to climb with leuprolide, despite the treatment dropping testosterone levels to castration levels after the initial testosterone spike. In HERO’s mean testosterone graph, about a week after either therapy is administered, the leuprolide arm saw a spike to more than 600ng/dL whereas this was under 50ng/dL with relugolix. Both arms have a median baseline of around 400ng/dL.

Relugolix approvable but moving patients off leuprolide unlikely to be straightforward

Despite the questions surrounding relugolix’s impact on CV issues, the drug is approvable based on HERO, experts said. The primary endpoint of sustained castration rate from day 29 to 337 was achieved by 96.7% versus 88.8% with relugolix and leuprolide, respectively (p<0.0001).

Once approved, the main obstacle for switching or general uptake for relugolix is its potentially significantly high copay, Maughan said. Patients who may benefit from a reduced risk in developing CV issues may not be able to afford the drug, Diecer noted. Copays can be as much as 20%, which would be burdensome especially for an expensive drug, he noted. Relugolix could play out similarly to Johnson & Johnson’s Erleada (apalutamide), an oral drug for castrate-resistant patients, wherein some patients cannot afford the copay, Maughan said. Erleada costs around $12,800 per 120 tablets.

Under the US’ Medicare program, relugolix would be classified under Medicare part D, which makes the medication available at a pharmacy, versus clinic-administered leuprolide, which is under Medicare part B, Maughan said. There is a risk that urology practices with a built-in pharmacy for income generation could unduly influence relugolix prescription rates, Stadler added. But clinicians should prescribe according to the data, Diecer noted.

In terms of patient preferences, leuprolide’s every three months dosing is more attractive but so is relugolix’s oral administration for some patients, as that would not require patients to go to the clinic, experts noted. Some 22.7% in both HERO arms are newly diagnosed patients. But new patients would also be offered many other available options like surgical castration, which is a one-time procedure, Stadler said. And if the patient prefers an oral treatment, Johnson & Johnson’s Zytiga (abiraterone) could be an option, he added.

Yet, oral therapies come with compliance issues, and a quick resurgence of testosterone is a potential concern, Diecer said. But relugolix’s time to testosterone recovery is not too immediate, and even 80% compliance should be sufficient for efficacy, Maughan noted.

Once treatment is completed, HERO shows patients have rapid testosterone resurgence, which is an advantage over leuprolide, Maughan said. In the testosterone recovery substudy of 184 patients, the mean testosterone measure 90 days post-treatment was 280ng/dL versus 50ng/dL with relugolix and leuprolide, respectively. HERO’s design classifies ≤50ng/dL as treatment castration. With leuprolide, some patients do not recover their testosterone levels once treatment stops or take around a year, Maughan said.

These data underscore relugolix’s use for localised disease, Maughan noted. A vast majority of patients are initially diagnosed with localised disease rather than metastatic disease, which is only about 10% at diagnosis, he explained. Around 26–27% of patients in both HERO arms had advanced localised disease unlikely to be cured by either surgery or radiation. Historical data show androgen ablation with radiation is superior to radiation alone, which could support relugolix in localised disease, Stadler said. The rationale is that radiation would target the localised tumour and androgen ablation would reduce prostate-specific antigen (PSA), a marker for the biochemical aspect of prostate cancer, noted Dr Benjamin Viglianti, assistant professor, radiology, Division of Nuclear Medicine, University of Michigan, Ann Arbor.

So far, Stadler noted, HERO data have not highlighted results specifically for localised patients. Lack of rapid testosterone resurgence once treatment stops can also open use off-label in patients who only need intermittent treatment of at least six months, Maughan noted. But, more data are needed as HERO did not recruit such patients, Stadler added.

Additionally, forthcoming data, due 3Qon relugolix’s potential to delay progression could potentially be a significant differentiation from leuprolide but would depend on the data quality, Diecer said. For example, delayed PSA resurgence is not as important as delay in metastasis or radiographic disease, he explained. If relugolix reports of a six-month delay in the latter two metrics versus leuprolide, this would be clinically significant, Diecer said. But Stadler and Maughan said this may be unlikely, with Maughan noting there is no precedence for differentiation.

Reynald Castaneda is Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.