Phase 2 Trial Assessing CPI-1205, Plus Xtandi, Begins Dosing Metastatic CRPC Patients

Phase 2 Trial Assessing CPI-1205, Plus Xtandi, Begins Dosing Metastatic CRPC Patients

Constellation Pharmaceuticals has begun patient dosing in the second part of a Phase 1b/2 trial testing its investigational inhibitor CPI-1205, in combination with Xtandi (enzalutamide), for the second-line treatment of metastatic castration-resistant prostate cancer patients (mCRPC), the company announced.

The ProSTAR trial (NCT03480646) was also expanded to include a third group in its Phase 2 part, which will test a combination of CPI-1205 plus Zytiga (abiraterone acetate) and prednisone in a similar patient population. The trial is continuing to recruit patients at sites across the U.S.

The decisions come after encouraging Phase 1b results, where CPI-1205 was well-tolerated by patients and showed preliminary signs of effectiveness.

“We are pleased that CPI-1205 achieved its Phase 1b endpoints in ProSTAR, demonstrating an encouraging safety profile and evidence of clinical activity,” Adrian Senderowicz, chief medical officer of Constellation Pharmaceuticals, said in a press release. “As we advance into the Phase 2 portion of the study, we believe combination therapy with CPI-1205 may provide a meaningful second-line treatment option to patients with metastatic castration-resistant prostate cancer, an area of significant unmet medical need.”

In early stages, prostate cancer is dependent on testosterone to grow. Patients who cannot receive surgery or radiation are thus treated with a kind of approach called androgen deprivation therapy, which lowers testosterone to undetectable levels.

Initial responses to hormone therapy are usually encouraging, but nearly half of patients acquire resistance, meaning their cancer is able to grow even with very low testosterone levels. At this point, they are considered to have castration-resistant prostate cancer (CRPC).

Therapies that target the androgen receptor — which is overly active in CRPC patients — have become the mainstay first-line treatment for patients who no longer respond to standard hormone therapy. But while up to 80% of patients respond to second-generation androgen receptor signaling inhibitors — which include Xtandi and Zytiga — many will also become resistant and experience disease progression.

Patients are then offered another inhibitor of the same kind or chemotherapy, but responses are only seen in 10% to 30% of them and are not sustainable.

The EZH2 molecule is involved in cancer progression in mCRPC patients and is thought to help prostate cancer cells gain resistance to androgen receptor inhibitors. Inhibiting its function could thus improve patient responses.

Consistently, preclinical studies of the EZH2 inhibitor CPI-1205 have shown it inhibits tumor growth and works in concert with inhibitors of androgen receptor signaling, such as Xtandi.

These findings led to researchers designing ProSTAR to determine if CPI-1205 was safe and improved the efficacy of Xtandi in metastatic CRPC patients who had progressed after receiving prior treatment with Zytiga.

The trial is two-fold. In the Phase 1 part, patients received escalating doses of CPI-1205 to determine the best dose for further testing. After this dose is found, researchers will include an additional 70 patients and randomly assign them to CPI-1205 plus Xtandi or Xtandi alone.

An additional group will treat 30 mCRPC patients, who failed Xtandi as their first-line treatment, with a combination of CPI-1205, Zytiga, and prednisone. This arm will have no control group, as only 4% of patients who receive Zytiga plus prednisone in this setting achieve a 50% reduction in their PSA levels.

“We are excited about expanding our opportunity to include an arm evaluating CPI-1205 in combination with abiraterone in the second-line setting, given that very few patients experience a 50% reduction in PSAs on second-line treatment with abiraterone and that time to progression in this setting is typically short,” Senderowicz said.

In the trial, the safety of both combinations will be assessed as a primary objective. Secondary goals include the proportion of patients with a 50% or higher reduction in their PSA levels, reduction in circulating tumor cells, response rates, time to progression, and time to new treatment for prostate cancer.