Cabozantinib for Prostate Cancer - A Renewed Hope

Cabozantinib, an oral tyrosine kinase inhibitor against MET and vascular endothelial growth factor receptor 2 (VEGFR2), is an agent that was initially met with enormous enthusiasm by the prostate cancer community. The early data showed dramatic bone scan responses, where bone metastases would almost magically disappear after cabozantinib treatment on subsequent restaging bone scans. As this was an unfamiliar, yet welcome phenomenon, the field eagerly began working on the development of this agent.

The initial publication with cabozantinib was reported in a Phase II randomized discontinuation trial and expansion cohort.¹ Patients (n=171) with metastatic castration-resistant prostate cancer (mCRPC) were treated with cabozantinib 100 mg PO QD and those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. The observed activity of cabozantinib led to the early cessation of randomization. However, this was due to 68% of patients having improved appearance on bone scan and 72% of patients with measurable disease having some level of regression. Ultimately, 31 patients with stable disease at week 12 were randomized with median progression-free survival (PFS) of 23.9 vs. 5.9 weeks for the cabozantinib vs. placebo arms (hazard ratio [HR] 0.12, p<0.001), respectively. A retrospective review identified the improvement of bone pain in 67% of evaluable patients with a decrease in narcotic use in 56%.

A second Phase II trial evaluated cabozantinib 100 mg (n=93) or 40 mg (n=51) PO QD dosing in a restricted post-chemotherapy metastatic castration-resistant prostate cancer population.² Bone scan responses were observed in 73% and 45% of patients, respectively; reductions in measurable disease were noted in 80% and 79% of patients, respectively. The median PFS was 10.8 months for the entire population. In regards to pain, 57% of patients experienced a clinically meaningful improvement in pain, while 55% had either a reduction or complete discontinuation of narcotic analgesics.³ The 40 mg PO QD dose required fewer dose reductions for toxicity.

The above promising Phase II results led to randomized Phase III trial development which, unfortunately, was not capable of demonstrating an overall survival benefit with cabozantinib in the COMET-1 trial. Specifically, 1,028 men with progressive mCRPC after prior docetaxel and abiraterone and/or enzalutamide were randomized 2:1 to cabozantinib 60 mg PO QD or prednisone 5 mg PO BID. Although radiographic PFS was 5.6 vs. 2.8 months (HR 0.48, p<0.001) in favor of cabozantinib over prednisone, respectively, overall survival was the primary endpoint. The median overall survival was 11.0 vs. 9.8 months (HR 0.90, p=0.213), lacking statistical significance, with cabozantinib vs. prednisone, respectively.

The COMET-1 negative results, unfortunately, led to the early termination of the randomized Phase III COMET-2 trial. The COMET-2 trial randomized men with painful bone mCRPC in the post-docetaxel and post abiraterone or enzalutamide disease state to cabozantinib 60 mg PO QD vs. mitoxantrone 12 mg/m² IV every three weeks plus prednisone 5 mg PO BID. The primary endpoint was pain response at six weeks with confirmation at week 12 with the goal of >30% decrease pain from baseline via the Brief Pain Inventory without increased narcotic use. At study closure, 119 patients were randomized. With only 69% of patients evaluable for the 12-week pain response endpoint, there was no significant difference between the two arms, with 15% vs. 17% (p=0.8) for cabozantinib vs. mitoxantrone with prednisone, respectively.⁴

Although cabozantinib has had successes in other malignancies with United States Federal Drug Administration (FDA) approvals in renal cell carcinoma,⁵ hepatocellular carcinoma,⁵ and medullary thyroid cancer,⁶ enthusiasm for single-agent use in prostate cancer was lost after the above experience. However, it was clear that there was antitumor activity. Therefore, it was reasonable to test novel combination therapy. Recently, the COSMIC-021 basket trial combined cabozantinib with atezolizumab, testing the concept that cabozantinib may promote an immune-permissive microenvironment. It is possible that tumor-infiltrating lymphocytes (TILs) could increase after cabozantinib treatment. Cohort 6 treated 44 mCRPC patients who had radiographic progression with measurable disease after prior abiraterone and/or enzalutamide.⁶ The primary endpoint of the overall RECIST 1.1 response rate was achieved by 32% of patients. Fatigue (50%), nausea (43%), decreased appetite (39%), diarrhea (39%), dysgeusia (34%), and palmar-plantar erythrodysesthesia (32%) were the most common treatment-related adverse events.

As a result of the above COSMIC-021 data, a randomized Phase III trial of cabozantinib vs. a second novel hormonal therapy agent has been launched and is termed the CONTACT-02 trial (NCT04446117).  However, other combinations with checkpoint inhibitors are being explored in clinical trials with prostate cancer patients in various disease states. See below for ongoing prostate cancer clinical trials studying cabozantinib.

Highlighted trials with Cabozantinib for prostate cancer patients

• Cabozantinib with nivolumab for advanced cancer and HIV patients (NCT04514484)
• CABIOS trial: Cabozantinib and androgen deprivation therapy/abiraterone with nivolumab for new metastatic hormone-sensitive prostate cancer (NCT04477512)
• CONTACT-02: Randomized Phase III trial of cabozantinib with atezolizumab vs. a second novel hormonal therapy (NCT04446117)
• SPARC: Cabozantinib followed by prostatectomy vs. immediate prostatectomy (NCT03964337)
• Cabozantinib with ipilimumab and nivolumab for rare genitourinary tumors (includes metastatic prostate and neuroendocrine histology) (NCT03866382)
• Phase I/II of cabozantinib with atezolizumab for solid tumors (including metastatic castration-resistant prostate cancer) (NCT03170960)