New Targeted Therapy Trial Opens, Part of PC-BETS Metastatic CRPC Study

New Targeted Therapy Trial Opens, Part of PC-BETS Metastatic CRPC Study

A trial opened to investigate CFI-400945, by Treadwell Therapeutics, as a potential oral therapy for people with metastatic castration-resistant prostate cancer (mCRPC), the company announced in a press release.

It is one of several sub-studies within a larger Phase 2 clinical trial (NCT03385655) that is evaluating various treatment candidates, including targeted therapies, immunotherapies, and chemotherapies, as possible precision treatments for mCRPC patients.

People enrolled first undergo a liquid biopsy to identify specific mutations evident in cancer cell DNA that is circulating freely in their blood. Based on biopsy results of these biomarkers and other indications, they then are matched to a sub-study, or treatment arm whose therapies they are seen as most likely to respond to.

Known as the PC-BETS trial and conducted by the Canadian Cancer Trials Group (CCTG), the large umbrella study is recruiting up to 500 patients at sites across Canada. Information on contacts and locations can be found here.

CFI-400945 is a selective and potent inhibitor of Polo-like kinase 4 (PLK4), a protein that regulates cell division and is overly produced in many cancers. By blocking this protein, the therapy aims to induce defects in cell division that result in cell death.

Results of animal studies suggest that cancers lacking the PTEN protein — a tumor suppressor protein that is often missing in prostate cancers — are more sensitive to CFI-400945 treatment. PTEN inactivation is a biomarker for this sub-study.

“We are very excited to see the initiation of this trial, that builds on preclinical work demonstrating an association between loss of the tumor suppressor PTEN, a common alteration in this disease setting, and response to CFI-400945,” said Mark Bray, PhD, Treadwell’s chief scientific officer and company co-founder.

PC-BETS is also evaluating other targeted treatment approaches, including ipatasertib, an AKT inhibitor by Rocheadavosertib, a WEE1 inhibitor, and savolitinib, a c-Met inhibitor, both by AstraZeneca; and Nubeqa (darolutamide), an androgen receptor inhibitor approved to treat non-metastatic CRPC, jointly developed by Bayer and Orion.

A combination of the immunotherapies Imfinzi (durvalumab) and tremelimumab is also being investigated in a sub-study, as is the platinum chemotherapy carboplatin.

“Our understanding of the molecular drivers of prostate cancer is increasing, and for some of these molecular variations we have few therapeutic options,” said Aaron R. Hansen, MD, a study chair at the Princess Margaret Cancer Center. “The innovative trial design of [PC-BETS] will match men with metastatic castration-resistant prostate cancer with agents designed to target their specific molecular abnormalities, in order to improve their outcomes.”

The trial’s primary goal to determine the clinical benefit of each treatment — defined as the proportion of patients who show a decline in their prostate serum antigen (PSA) levels of 50% or greater, a partial or complete response to treatment, or stable disease for at least 12 weeks.

Secondary measures include the severity and the number of adverse effects, the proportion of patients responding to treatment, and the effects of each drug on PSA levels.

Researchers shared data on the first 250 screened patients at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, in the presentation “Prostate cancer biomarker enrichment and treatment selection (PC-BETS) study: A Canadian cancer trials group phase II umbrella trial for metastatic castration-resistant prostate cancer (mCRPC).”

Among the screened patients, 169 had detectable tumor DNA in their blood. The most common genetic alterations found were those in the androgen receptor (AR) gene (73%), TP53 mutations (49%), mutations affecting the PTEN/PI3K pathway (35%), and those in genes involved in DNA repair mechanisms (23%).

At data collection for the presentation, the trial had enrolled 83 patients, including 46 who were positive for a gene alteration seen as a biomarker, and 37 who were negative. Their median age was 70, and their cancer had progressed despite treatment with an androgen receptor inhibitor. Metastases in 17% of these people were in soft-tissues organs like the liver, which can lead to organ failure.

Sixteen people were assigned to the palbociclib treatment arm, 19 to adavosertib, 12 to savolitinib, and 36 to Nubeqa. At the time of the analysis, a clinical benefit was observed in one biomarker negative patient on adavosertib, and six patients (five with AR alterations, one who was biomarker negative) given Nubeqa.

Adverse events reported to date were in line with expected side effects of these therapies.

In addition to CCTG, this study is also supported by the Canadian Cancer Society, Prostate Cancer Canada, and the Movember Foundation.