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18-02-2022 | ASCO GU 2022 | Conference coverage | News

Early mCRPC promise shown for novel CYP11A1 inhibitor

Author: Shreeya Nanda

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medwireNews: ODM-208, a novel nonsteroidal inhibitor of CYP11A1, has demonstrated promising antitumor activity in previously treated patients with metastatic castration-resistant prostate cancer (mCRPC) enrolled in the first-in-human CYPIDES study.

The activity was especially notable in men with disease positive for androgen receptor (AR) mutations, study author Karim Fizazi (Institut Gustave Roussy, Villejuif, France) told delegates of the 2022 ASCO Genitourinary Cancers Symposium, held in San Francisco, California, USA.

Outlining the background to the study, he explained that “the [AR] axis remains activated and is often responsible for cancer progression in men with CRPC evolving after drugs such as abiraterone and enzalutamide.”

Activating AR mutations in ligand binding domains (LBDs) are a known mechanism of resistance and nonandrogenic steroid hormones can also activate the AR axis, added Fizazi, leading the investigators to hypothesize that “complete steroid biosynthesis inhibition” via the selective CYP11A1 inhibitor ODM-208 could be beneficial in this patient population.

The dose-finding phase 1 part of the trial included 44 patients aged a median of 70 years with progressive disease who had received at least one prior AR axis inhibitor and at least one line of taxane-based chemotherapy; 55% had received both abiraterone and enzalutamide and 57% had received cabazitaxel.

ODM-208 was administered orally alongside androgen deprivation therapy and glucocorticoid (primarily dexamethasone) and mineralocorticoid (fludrocortisone) replacement therapy. The initial ODM-208 dose of 50 mg twice daily, based on animal experiments, achieved maximal steroid suppression so the dose was de-escalated to 3 mg twice daily, the presenter explained.

Treatment with ODM-208 led to a prostate-specific antigen (PSA) response, defined as a decline in levels of more than 50%, in 32% of the study participants, with the response rate rising to 68% when just the 17 men harboring AR LBD mutations were considered. By contrast, the PSA response rate was just 8% in those without such mutations.

Fizazi highlighted that prolonged responses were seen, with five patients remaining on treatment after a year.

With regard to the safety profile, one dose-limiting toxicity (adrenal insufficiency) was observed in a patient receiving the 50 mg twice daily dose.

Unsurprisingly, adrenal insufficiency was the most common adverse event, with nearly a third (31.8%) of participants experiencing it and hospitalized as a result, said the presenter. He pointed out, however, that all cases were reversible after transient discontinuation of ODM-208 and intravenous administration of hydrocortisone and fluids.

Fizazi concluded that to circumvent the adrenal insufficiency, the ongoing dose-expansion phase of the trial is using a 5 mg twice daily dose of the drug, with a wider range of dexamethasone doses and a higher dose of fludrocortisone, and “this appears to be successful.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

ASCO Genitourinary Cancers Symposium; San Francisco, California, USA: 17–19 February 2022

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