First Patient Dosed in Early Trial Testing ORIC-101, Xtandi Combo for Metastatic Prostate Cancer

First Patient Dosed in Early Trial Testing ORIC-101, Xtandi Combo for Metastatic Prostate Cancer

A Phase 1b trial has started dosing patients to study whether Oric Pharmaceutical’s ORIC-101 — which inhibits the glucocorticoid receptor — is able to overcome prostate cancer resistance to Xtandi (enzalutamide), the company announced.

The trial (NCT04033328) is testing a combination of ORIC-101 plus Xtandi in men whose metastatic prostate cancer is progressing while on Xtandi treatment. Ongoing at the Carolina Urologic Research Center, in South Carolina, it is expected to recruit a total of 90 participants. More information on enrollment can be found here.

“Despite the introduction of novel antiandrogen therapies for the treatment of prostate cancer, such as enzalutamide, the majority of responsive patients will ultimately become treatment resistant, resulting in poor prognoses for men diagnosed with this devastating condition,” Pratik S. Multani, MD, chief medical officer at Oric, said in a press release.

“We are excited to evaluate the therapeutic potential of ORIC-101 to overcome what we believe may be a key mechanism of resistance to antiandrogen therapy,” Multani added.

Xtandi, developed by Astellas Pharma and Pfizer, is a form of hormone therapy that seeks to prevent male hormones from sending chemical signals that stimulate cancer growth; it does so by blocking the activity of their receptor.

The treatment is developed for advanced forms of prostate cancer, including those that still respond to androgen receptor therapy (ADT) — a treatment that lowers testosterone levels — and those that don’t.

Due to its widespread use, resistance to Xtandi has become a major clinical problem. Some studies have identified a mutation in the androgen receptor that renders Xtandi ineffective. But more recently, a team led by Charles Sawyers, MD, Oric’s co-founder, also implicated the glucocorticoid receptor in this mechanism of resistance.

In fact, prostate cancer cells became resistant to Xtandi by increasing the amount of this receptor, which activated a set of genes that helped prostate cancer cells proliferate. In their study, an antagonist of the glucocorticoid receptor was enough to restore sensitivity to Xtandi.

“Just as the glucocorticoid receptor has been linked to treatment resistance for multiple classes of chemotherapeutics across a variety of solid tumors, there are also strong scientific rationale and preclinical evidence supporting its linkage to prostate cancer resistance,” said Jacob M. Chacko, MD, Oric’s CEO.

ORIC‐101 is a potent and selective small molecule that targets and inhibits the glucocorticoid receptor signaling. In preclinical studies, ORIC‐101 was able to rescue sensitivity to Xtandi in prostate cancer models that were initially resistant to the treatment. Two Phase 1a studies with more than 50 healthy volunteers also demonstrated that ORIC-101 was safe and well-tolerated.

The open label, Phase 1b trial was designed to evaluate the safety and the pharmacokinetics and pharmacodynamics profile of oral ORIC-101 in combination with Xtandi in men whose cancer is progressing while on Xtandi. The trial also is assessing early evidence of antitumor activity in this patient population.

Pharmacokinetics measures how a therapy behaves inside the body — its absorption, distribution, metabolism and excretion. Pharmacodynamics studies the biochemical, physiologic, and molecular effects of the treatment on the body.

The trial has a first dose-escalation phase to assess the optimal ORIC-101 dose for additional studies. That is followed by an expansion phase designed to assess the safety and efficacy of ORIC-101 at the selected dose in groups of patients whose cancers have different glucocorticoid receptor levels.

“We are delighted to collaborate with Astellas on this important study assessing the potential of ORIC-101 to benefit patients with metastatic prostate cancer that has progressed on enzalutamide, for which there are limited treatment options today,” Chacko said.

“Enrollment of the first patient in this Phase 1b clinical trial of ORIC-101 marks the second clinical trial for this program and another major milestone for ORIC,” he added.

Another Phase 1b trial (NCT03928314) is assessing a combination of ORIC-101 in combination with the chemotherapy agent Abraxane (nab-paclitaxel) — developed by Celgene — in people with advanced solid tumors. That trial is recruiting up to 42 participants at four sites in the U.S. More information on contacts and locations can be found here.