On May 28, 2025 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported potentially best-in-class preliminary efficacy and safety data from the ongoing Phase 1b trial of once daily ORIC-944 in combination with androgen receptor (AR) inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC) (Press release, ORIC Pharmaceuticals, MAY 28, 2025, View Source [SID1234653448]).
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"These ORIC-944 combination data demonstrate substantial clinical activity with both AR inhibitors, apalutamide and darolutamide, through early measures of efficacy (PSA50 and PSA90 response rates) and a safety profile consisting almost entirely of mild to moderate GI related adverse events, making it highly suitable for potential long term dosing," said Pratik S. Multani, M.D., chief medical officer.
"The data generated to date continue to demonstrate the potential of ORIC-944 to be a best-in-class PRC2 inhibitor that may benefit a broad range of patients with prostate cancer," said Jacob M. Chacko, M.D., president and chief executive officer. "The efficacy and safety data presented today compare favorably to other PRC2 inhibitor data presented earlier this year. We look forward to subsequent updates from the dose exploration and dose optimization portion of the Phase 1b trial over the next three quarters as we move towards initiating our first global registrational trial in 1H 2026."
ORIC-944 Phase 1b Trial Design
ORIC-944 is being evaluated in a Phase 1b dose exploration trial in combination with ERLEADA (apalutamide), Johnson & Johnson’s AR inhibitor, and NUBEQA (darolutamide), Bayer’s AR inhibitor, in patients with mCRPC. Patients are eligible if they have received prior treatment with an androgen receptor pathway inhibitor (ARPI) and up to one prior chemotherapy. The primary objectives of the trial are to determine the recommended Phase 2 dose (RP2D), and additional objectives include safety, tolerability, pharmacokinetics, and preliminary clinical activity.
ORIC-944 Phase 1b Dose Exploration Data
Data include 17 patients with mCRPC previously treated with a median of three lines of prior therapy, including abiraterone, up to one prior line of chemotherapy, and a variety of other approved and investigational treatment regimens. This median does not include androgen deprivation therapy or first-generation androgen receptor deprivation therapy. Patients were treated once daily with 400 mg, 600 mg, or 800 mg of ORIC-944 in combination with 240 mg of apalutamide once daily or with 600 mg of darolutamide twice daily. PSA response data are as of May 9, 2025.
Preliminary activity analysis
59% of patients (10/17) achieved a PSA50 response and nearly all patients with a PSA50 response were confirmed one month later, for a confirmed PSA50 response rate of 47% (8/17), which does not include one additional PSA response pending confirmation. 24% of patients (4/17) achieved a PSA90 response, all of which were subsequently confirmed.
PSA responses were observed across all ORIC-944 dose levels and were also observed at comparable rates in combination with apalutamide or with darolutamide. The majority of patients are still ongoing with multiple patients approaching one year or more on therapy. Further dose exploration is ongoing.
Preliminary safety analysis
ORIC-944 in combination with apalutamide or with darolutamide has been generally well tolerated to date, with a vast majority of adverse events (AEs) Grade 1 or 2 in severity and consistent with PRC2 and AR inhibition. As of April 22, 2025, diarrhea was the most common treatment-related AE, occurring in 53% of patients (9/17) across all dose levels with only one patient experiencing a Grade 3 event. There were no Grade 4 or Grade 5 treatment-related AEs attributed to ORIC-944 with apalutamide or with darolutamide.
Next Steps
Following completion of the Phase 1b dose exploration portion of the trial expected in mid-2025, the company plans to evaluate two candidate RP2Ds for each combination in the dose optimization portion of the trial in 2H 2025. Data from the dose optimization portion of the trial will inform the choice of ORIC-944 dose to advance in combination with apalutamide or with darolutamide in the first global Phase 3 registrational trial in mCRPC that the company expects to initiate in 1H 2026.
Corporate Update
The company announced a concurrent $125 million private placement financing that it expects will extend cash runway into the second half of 2027 and through the anticipated primary endpoint readout from the first ORIC-944 Phase 3 registrational trial in mCRPC. The financing is expected to close on May 29, 2025, subject to customary closing conditions.
Conference Call and Webcast Details
ORIC will host a conference call and webcast today at 4:30 p.m. ET. To join the conference call via phone and participate in the live Q&A session, please pre-register online here to receive a telephone number and unique passcode required to enter the call. A live webcast and audio archive of the conference call will be available through the investor section of the company’s website at www.oricpharma.com. The webcast will be available for replay for 90 days following the presentation.
About ORIC-944
ORIC-944 is a potent and selective allosteric inhibitor of the polycomb repressive complex 2 (PRC2) via the embryonic ectoderm development (EED) subunit that demonstrates best-in-class drug properties in preclinical studies, including potency, solubility, and pharmacokinetics, with half-life supporting once daily dosing. ORIC-944 was initially evaluated as a single agent in a Phase 1b trial in patients with advanced prostate cancer and demonstrated potential best-in-class drug properties, including clinical half-life of approximately 20 hours, robust target engagement and a favorable safety profile. ORIC-944 continues to further demonstrate a potential best-in-class profile with positive interim PSA response data generated in an ongoing Phase 1b trial in combination with ERLEADA (apalutamide) and in combination with NUBEQA (darolutamide) for prostate cancer (NCT05413421).