Apalutamide

Oric Pharmaceuticals on Tuesday detailed its plans to advance a PRC2 inhibitor into a registrational program for prostate cancer after sharing results from a Phase 1b trial. But the company’s shares $ORIC dropped by as much as 25% before market open Wednesday as investors had reservations about the biotech’s choice of androgen receptor inhibitor it will combine the investigational drug with. Oric said it plans to advance its candidate, known as rinzimetostat, and Bayer’s Nubeqa into a Phase 3 study. The trial will enroll 600 patients with metastatic castration-resistant prostate cancer (mCRPC) across more than 20 countries. It is set to start in the first half of this year. Jefferies analysts wrote Wednesday that the negative stock move might be due to onlookers thinking that Johnson & Johnson’s Erleada would have been a “better fit strategically” than Nubeqa. Results from a recent head-to-head real-world analysis show Erleada cut the risk of death by 51% compared with Nubeqa in certain prostate cancer patients, although they aren’t the same ones Oric is targeting. Oric’s early-phase trial recruited mCRPC patients who had a median two prior lines of therapy, including previous treatment with abiraterone. The analysts wrote that Oric decided to opt for Nubeqa because it has a lower risk of drug-drug interactions with the investigational drug compared with Erleada. Oric’s choice of combination approach was also based on data from the Phase 1b trial, which tested two different doses of rinzimetostat with Nubeqa, but also with Erleada. The Tuesday release did not report data with Erleada. Results from the Phase 1b trial also led to Oric choosing the lower dose (400 mg) of rinzimetostat versus a higher one (600 mg). The company said that the higher dose was associated with a “modestly higher rate of adverse events.” The most common side effects at the lower dose were fatigue, diarrhea and nausea. There were no grade 4 or 5 events associated with the regimen. The company added both doses had “comparable efficacy,” although the Tuesday data were not split by dose level. Of the 18 evaluable patients treated with the investigational combo of rinzimetostat and Nubeqa, 84% were still alive with no disease progression at five months with a median follow-up of 4.9 months. With the caveat of cross-trial comparison, the Tuesday data are “consistent with” the results attained by Pfizer’s candidate, called mevrometostat, in combination with Xtandi in a Phase 3 trial, despite Oric patients being more heavily pretreated, the Jefferies analysts said. Both rinzimetostat and mevrometostat inhibit the PRC2 complex, but via different subunits — rinzimetostat targets EED, while mevrometostat acts on EZH2. Editor’s note: This story was updated to clarify drug mechanisms.

ORIC Pharmaceuticals said Tuesday it will start a registrational study this half for its experimental metastatic castration-resistant prostate cancer (mCRPC) treatment, rinzimetostat (formerly ORIC-944), as it looks to best a potential rival from Pfizer. The pharma is developing mevrometostat, an EZH2 inhibitor, also for mCRPR. Last year, Phase I data showed mevrometostat reduced the risk of progression or death by 49% when combined with Xtandi (enzalutamide) in patients with mCRPC, which analysts at the time called "very positive" for ORIC. The biotech's rinzimetostat is an allosteric inhibitor of PRC2, a chromatin modifying enzyme complex whose subunits include EZH2 and EED, the latter of which ORIC's compound binds to.While ORIC reported seemingly positive Phase Ib data for rinzimetostat to justify its move into Phase III testing, the company's shares plummeted 41% on Wednesday — though some investors questioned the drastic drop's rationale. "We’re not sure why the stock is selling off," Oppenheimer analysts wrote in a note. "The efficacy looks competitive to mevrometostat."ORIC said in a company release that the early efficacy data are "suggestive of meaningful and durable clinical benefit…compared to competitor data and historical outcomes with approved therapies."Survival and safety dataThe early-stage study evaluated 400-mg and 600-mg once-daily doses of rinzimetostat in combination with an AR inhibitor, either Johnson & Johnson's Nubeqa (darolutamide) or Bayer’s Erleada (apalutamide). An exposure-response analysis showed that the two dose levels had comparable efficacy, but it "identified statistically significant relationships between higher drug exposure and toxicities as well as increased rates of treatment modifications, clearly favouring the 400-mg dose on the basis of safety." As a result, ORIC has selected the 400-mg dose of rinzimetostat in combination with the standard, 600-mg twice daily dose of Nubeqa as the recommended Phase III dose. The drugmaker on Tuesday shared data from the 18 patients who received that specific cocktail in the Phase Ib trial.After a median follow-up of 4.9 months, patients achieved "landmark" radiographic progression-free survival (rPFS) rates of 93%, 84% and 84% at three, four and five months, respectively. According to ORIC, the results are consistent with data for mevrometostat in post-abiraterone mCRPC patients, and superior standard-of-care therapies.Additionally, in a subset of 15 patients with at least one post-baseline assessment as of the Jan. 16 cutoff, seven patients (47%) achieved a PSA50 response, with five (33%) confirmed responses. ORIC also evaluated molecular responses in 14 patients with detectable circulating tumour DNA (ctDNA) at baseline. In that group, 10 patients (71%) achieved a >50% ctDNA reduction.The findings "provide confirmatory evidence that support rinzimetostat’s potential best-in-disease clinical profile, reinforcing its path towards becoming a practice-changing therapy for patients with prostate cancer," said CEO Jacob M. Chacko in a company release, noting that the candidate demonstrated "a markedly cleaner safety profile than competitor regimens."The Oppenheimer analysts also homed in on the safety data, calling it "the real differentiator." "Most docs we’ve spoken to say mevrometostat has real tolerability issues, driven by diarrhoea and dysgeusia," they wrote. "Rinzimetostat chops those in half." ORIC reported that the most common treatment-released adverse events (TRAEs) in patients receiving the 400-mg dose of rinzimetostat were fatigue (39%), diarrhoea (22%) and nausea (22%). There was one case of a grade 3 TRAE, and no grade 4 or 5 AEs were linked to the treatment regimen. The company is planning to enrol 600 patients with mCRPC patients who were previously treated with abiraterone in the Phase III Himalayas-1 trial, comparing the rinzimetostat-Nubeqa duo against physician’s choice of an AR inhibitor or chemotherapy. The study's primary endpoint will be rPFS, with overall survival as the key secondary measure.