GU cancer

HERO compares androgen deprivation therapies in prostate cancer

Prof Henry Woo

An oral androgen deprivation therapy (ADT) taken once daily maintained castrate levels of testosterone at a higher rate and was associated with lower risk of major adverse cardiovascular events (MACE) in men with advanced prostrate cancer compared to a standard care injectable ADT, a phase III trial found.

Data from the HERO trial presented at the ASCO20 Virtual Scientific Program compared treatment with the oral GnRH receptor antagonist relugolix with the injectable GnRH agonist leuprolide.

Presenting the data Professor Neale Shore of the Carolina Urologic Research Centre in the US, said the study met its primary endpoint, demonstrating that castration at 48 weeks was maintained in 96.7% of those assigned to relugolix compared to 88.8% of those on leuprolide, meeting prespecified criteria for both non-inferiority and superiority (P<0.001).

Overall, 934 patients, including those from Australia, with advanced prostate cancer underwent 2:1 randomisation and received 48 weeks of either relugolix 120 mg orally once daily after a one-time 360 milligram loading dose or leuprolide 22.5 milligram injection every three months.

Relugolix also achieved castration levels of testosterone as early as day four of the study with rapid testosterone recovery after discontinuation – 54% of patients in the relugolix group achieved testosterone recovery to at least 280 nanograms per decilitre within 90 days compared to 3% in the leuprolide group.

The agent may have potential as a new standard of care for testosterone suppression in patients with advanced disease, suggests Professor Shore noting cardiovascular mortality is the leading cause of death for patients with prostate cancer.

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). 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).

“This reflected an almost five-fold increase in odds of having a MACE event in men with a prior history treated with leuprolide compared with relugolix,” says Professor Shore.

Practice changing?

Professor Henry Woo, Professor of Robotic Cancer Surgery and director of uro-oncology at Chris O’Brien Life House, was an investigator on the Australian arm of the trial.

In an interview with the limbic he said the findings suggest that patients who already have existing cardiovascular disease, or have significant risk factors for cardiovascular disease, should be considered for relugolix over leuprolide – but he’s hesitant about labelling the drug ‘practice changing’.

“It is easy to reach a conclusion that because of potential advantages of a more efficient testosterone suppression we should be using relugolix, but we have to consider how important that is going to be from a practical perspective.

I don’t think it matters what form of LHRH agonist or antagonist is prescribed when ADT is to be commenced,” he said adding that the greater concern is whether castrate levels of testosterone are achieved or not,” he said pointing out that the benefits seen with relugolix will of course only be achieved if patients take the drug consistently.

The problem of compliance was overcome in the trial says Professor Woo with the use of a smart bottle, which reminds patients to take their medication. It’s a factor that wasn’t mentioned in the paper, he says.

“As to whether that played a significant role in maintaining compliance is yet to be determined.  Additionally, it always has to be remembered that in a setting of a clinical trial, compliance is always going to be better because patients are being so closely monitored. There are a lot of advantages to having an injectable form of the drug where patients can have the injection and forget about it for the next three months.”

For Professor Woo, the real test will be at the post marketing study, which would look at the impact of whether patients were able to take the medication regularly enough to maintain appropriate testosterone levels.

“We already know that compliance with oral medications can be problematic and having a drug with relatively rapid onset and rapid washout needs to be factored in to the decision to offer relugolix instead of conventional injectable LHRH agonists.

Part of our standard of care is to measure testosterone levels whilst on ADT and if castrate levels are achieved then there’s no reason why you couldn’t continue with the injectable form of the treatment; if there is inadequate testosterone suppression, then you would need to think about changing the formulation,” he said adding that the drug degarelix could also be considered.

“We do have another drug that reduces the risk of cardiovascular events compared to standard LHRH agonists in the form of degarelix – an LHRH antagonist. In high risk patients it can reduce cardiovascular events compared to LHRH agonists so having another drug in our armamentarium is welcome news”

In the HERO trial patients on the oral drug achieved rapid testosterone reductions, with a higher proportion reaching castrate levels (<50 ng per decilitre) at days 4 (56.0% vs 0%) and 15 (98.7% vs 12.0%) versus leuprolide (P<0.001 for both).

Meanwhile 79.4% of patients in the relogolix arm had a PSA response at day 15 compared to 19.8% with leuprolide (P<0.001).  At week 24, FSH suppression was also improved with relugolix (mean 1.72 vs 5.95 IU/L, P<0.0001).

Early relief from side effects

Professor Woo said in men likely to benefit from a prompt fall in testosterone levels or in circumstances where men may be eager to see a testosterone recovery and therefore possibly earlier relief from some of the side effects of androgen deprivation therapy relugolix may be beneficial.

“During the Covid 19 pandemic, large numbers of men with localised prostate cancer were being placed on androgen deprivation therapy to place them in a holding pattern until surgery could be offered.  This is one example of a group of men who could benefit from a form of ADT with a rapid washout of adverse effects.”

Meanwhile Professor Shore pointed out that because relugolix suppresses both LH and FSH by directly inhibiting pituitary GnRH receptors it doesn’t cause the early testosterone surge seen with luteinising hormone-releasing hormone (LHRH) agonists, which can lead to disease flare.

Professor Woo told the limbic that many men could avoid additional drug therapy to treat testosterone flare as a result.

“When we use conventional LHRH agonist treatment, we have to be mindful of the potential clinical impact of any flare in testosterone levels. To counter this effect we usually administer a nonsteroidal antiandrogen such as bicalutamide. The rapid fall in testosterone levels associated with relugolix will mean that many men could avoid the need for additional drug treatment for flare coverage.”

As for adverse events the overall incidence was comparable between the two treatment groups with over 90% of patients in both groups experiencing at least one adverse event, notes Professor Shore.

The most common adverse events in both groups were consistent with the known consequences of ADT, including hot flushes that occurred in slightly more than half of the patients in the study. Diarrhoea was reported in a higher proportion of patients in the oral relugolix group than in the injectable leuprolide group. However, all diarrhoea events were mild or moderate grade one or grade two.

Meanwhile, 18% of patients in the relugolix arm and 20.5% in the leuprolide arm experienced grade 3 or greater adverse events. Fatal events were infrequent and were reported in 1.1% of patients in the relugolix group and 2.9% in the leuprolide group.

Commenting on medication compliance Professor Shore said that was greater than 99% for both agents.

“Relugolix has a long half-life, and even in real-world use we anticipate similar suppression results in patients appropriate for oral therapy.”

The study was also published online simultaneously in the NEJM

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