ESMO: Exelixis pushes FDA prostate cancer bid despite survival miss; Ipsen drops EU plan

Exelixis and its partner Ipsen have taken different regulatory paths concerning their combination treatment of Cabometyx and Tecentriq for metastatic castration-resistant prostate cancer (mCRPC). Despite the treatment failing to achieve a statistically significant extension in patient survival in a phase 3 trial, Exelixis plans to seek approval from the FDA. This decision is based on a numerical improvement in overall survival (OS) seen in the trial, which showed an 11% reduction in death risk compared to a change of novel hormonal therapy. According to the final analysis of the CONTACT-02 trial, presented at the European Society for Medical Oncology (ESMO) 2024 meeting, patients receiving the combo lived a median of 14.8 months, slightly less than the control group's 15 months.

CONTACT-02 is still viewed positively because it met its other primary endpoint, progression-free survival (PFS), earlier. PFS is considered a clinically relevant and approvable metric in prostate cancer. In January, the combination treatment was reported to reduce the risk of disease progression or death by 35% compared to a second novel hormonal therapy, with a then wider numerical survival advantage of 21%.

The landscape for treating mCRPC is changing, with multiple options available such as androgen receptor inhibitors, chemotherapy, PARP inhibitors, immune checkpoint inhibitors, and radioligand therapy. This evolution makes demonstrating an improvement in OS challenging due to patients switching treatments upon disease progression.

Back in 2014, Cabometyx as a single agent did not significantly improve OS in heavily pretreated mCRPC patients, despite showing notable PFS improvement in an exploratory analysis. This failure led to a significant reduction in Exelixis’ workforce. In the CONTACT-02 trial, a similar number of patients received subsequent therapies, primarily follow-on chemotherapy. Dr. Neeraj Agarwal from the University of Utah Health noted that the trial enrolled a population with a poor prognosis and high-risk factors, including a significant portion with liver metastases.

The combination treatment showed efficacy in high-risk patients. Among those with liver metastases, the regimen reduced the risk of death by 32%. For patients with bone metastases, which represented about three-quarters of the trial population, the risk of death was lowered by 21%. However, in patients without bone metastases, those on the combination treatment had shorter survival compared to the control group.

Exelixis aims to file for FDA approval of the treatment regimen this year. However, the specifics of the application and potential indications are yet to be determined. On the other hand, Ipsen, responsible for Cabometyx outside the U.S. and Japan, will not pursue approvals for this combination in their territories, citing regulatory challenges.

Dr. Rana McKay from the University of California, San Diego, highlighted the increasing prevalence of liver metastases in advanced prostate cancer, indicating an unmet medical need due to worse outcomes and limited treatment options. She emphasized that regulatory approvals in mCRPC settings typically consider the totality of data, including PFS, OS, safety, toxicity, and quality of life.

Regarding toxicity, grades 3 or 4 treatment-related adverse events were higher in the combination group (40%) compared to the control group (8%), and treatment discontinuation due to adverse events was also higher in the combination arm. No treatment-related deaths were reported. If approved by the FDA, the combination treatment is expected to see most use among patients with liver metastases.

At the same ESMO 2024 meeting, an update on the phase 3 CABINET trial for Cabometyx in advanced neuroendocrine tumors was presented. Cabometyx showed significant efficacy, reducing the risk of progression or death by 77% in advanced pancreatic neuroendocrine tumors (pNET) and by 62% in advanced extra-pancreatic neuroendocrine tumors (epNET). Despite numerical improvements in overall survival, these did not reach statistical significance. The trial had previously stopped early due to strong efficacy results, underscoring Cabometyx's potential clinical utility in late-line neuroendocrine tumors.