CONTACT-02 – Signs of Activity with Cabozantinib for Prostate Cancer, Yet There Is Still More to Be Desired

Cabozantinib, an oral tyrosine kinase inhibitor against MET and vascular endothelial growth factor receptor 2 (VEGFR2), is an agent that has had success in multiple tumor types, such as renal cell, hepatocellular and medullary thyroid cancer.  There have been multiple randomized phase 3 trial attempts for patients with prostate cancer.  The COMET-1 trial randomized 1,028 men in the post docetaxel and androgen pathway inhibitor (ARPI) disease state 2:1 to cabozatinib 60 mg po qd or prednisone 5 mg po BID.  Although radiographic PFS was statistically significant in favor of cabozantinib, overall survival was negative.¹  This led to the early termination of the randomized phase 3 COMET-2 trial, which was studying men with symptomatic bone metastatic castration-resistant prostate cancer, also in the post-docetaxel and post-ARPI disease state.

With only 119 patients randomized to cabozantinib 60 mg po qd vs. mitoxantrone 12 mg/m² IV q3wk plus prednisone 5 mg po bid, only 69% of patients were evaluable for the primary endpoint of >30% pain response; not surprisingly, there was no significant difference found between the 2 groups.²

Fast forward the clock many years, and the concept of a combination of cabozantinib with immune-oncology therapy was tested in the COSMIC-021 basket trial.  In patients with metastatic castration-resistant prostate cancer, 32% of patients, previously treated with an ARPI, had a RECIST 1.1 response.³  This served as the basis for the CONTACT-02 trial, comparing cabozantinib vs. a second ARPI in the pre-docetaxel metastatic castration-resistant prostate cancer disease state.  The initial presentation at the Genitourinary Cancers Symposium 2024 revealed a statistically significant benefit to the combination over the second ARPI, with a median PFS of 6.3 vs. 4.2 months, HR 0.65, 95% CI 0.50 – 0.84; p=0.0007, respectively.⁴  The final overall survival data was presented recently at the 2024 European Society of Medical Oncology (ESMO) meeting, showing a median overall survival of 14.8 vs. 15.0 months (HR 0.89, 95% CI 0.72 – 1.10; p=0.30) in the cabozantinib plus atezolizumab arm compared to the second ARPI arm, respectively.⁵  Interestingly, subset analysis for patients with liver metastasis was more promising with median overall survival of 12.2 vs. 7.1 months (HR 0.68, 95% CI 0.47 – 1.00; p=0.051) for the cabozantinib plus atezolizumab arm compared to the second ARPI arm, respectively.  Similarly, the subset analysis for patients with bone metastasis showed median overall survival 13.8 vs. 11.6 months (HR 0.79, 95% CI 0.63 – 1.00; p=0.046).

The above results have led to much discussion in our field.  A common viewpoint is that it might be nice to have a new regimen specifically for the population harboring liver metastasis.  It is a patient population with a poor prognosis and is an unmet need in our field.  However, it is also a population where most clinicians would lean towards use of chemotherapy, rather than another ARPI.  As a result, many questions can be raised about the adequacy of the control arm.  It will be interesting to see what regulatory agencies determine.

In the meantime, there are other ongoing biomarker selected and combination therapy clinical trials with cabozantinib for prostate cancer patients in various disease states.  See below for these actively accruing prostate cancer clinic trials studying cabozantinib combination therapy.

Highlighted trials using Cabozantinib for patients with prostate cancer

• Cabozantinib with molecular selection (mutation or amplification in MET, KIT, RET, VEGFR-1, VEGFR-2, VEGFR-3, FLT3, AXL, TRKB, or TIE2) for metastatic castration-resistant prostate cancer (NCT04631744)
• CaboLu Trial – Cabozantinib with ¹⁷⁷Lu-PSMA-617 for metastatic castration-resistant prostate cancer (NCT05613894)
• AtezoCab Trial – Cabozantinib with atezolizumab for metastatic castration-resistant prostate cancer (NCT05502315)
• CANOPY trial – Cabozantinib followed by prostatectomy vs. immediate prostatectomy (NCT03964337)
• Cabozantinib with ipilumumab and nivolumab for rare genitourinary tumors (includes neuroendocrine prostate histology) (NCT03866382)

Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References

1. Smith M, et al. Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1. J Clin Oncol 2016; 34:3005-13.
2. Basch E, et al. Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer: A Randomized Phase 3 Trial with a Primary Pain Endpoint. Eur Urol 2019; 75:929-37.
3. Agarwal N, et al. Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021). Lancet Oncol 2022; 23:899-909.
4. Agarwal N, et al. J Clin Oncol 2024; 42 no. 4_suppl:517a.
5. Agarwal N, et al. Cabozantinib (C) plus atezolizumab (A) versus 2nd novel hormonal therapy (NHT) in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC): Final overall survival (OS) results of the phase III, randomized, CONTACT-02 study. ESMO 2024; Abstract LBA67.