Cabozantinib plus atezolizumab may represent a novel option for patients progressing on first-line hormonal therapy
Although immunotherapy has demonstrated remarkable efficacy in many solid tumours, its performance in metastatic prostate cancer has been disappointing so far. As presented at the American Society of Clinical Oncology 2024 Genitourinary Cancers Symposium, results from the phase III CONTACT-02 trial (NCT04446117) reported a statistically significant improvement in progression-free survival (PFS) with the multi-targeted tyrosine-kinase inhibitor (TKI) cabozantinib plus the anti-PD-L1 inhibitor atezolizumab in direct comparison with enzalutamide as second androgen-receptor pathway inhibitor (ARPI) in ARPI-pre-treated patients with metastatic castration-resistant prostate cancer (mCRPC) and a poor prognosis.
In the study, the clinical efficacy of the combination therapy in terms of PFS and overall survival (OS) as co-primary endpoints was evaluated against a second novel hormonal therapy in 507 patients who had measurable extra-pelvic soft tissue metastasis after progression on one prior treatment with hormonal agents. The PFS analysis was conducted in the first 400 randomised patients in the intent-to-treat population and per protocol.
At a median follow-up of 14.3 months, the median PFS was 6.3 months for cabozantinib plus atezolizumab compared with 4.2 months for second ARPI therapy (HR, 0.65; 95% CI, 0.50–0.84; p=0.0007). A PFS benefit was also observed across prespecified subgroups including in patients with liver metastasis, prior docetaxel therapy, and bone metastasis.
Data presented provide for the first time a positive signal for the use of the immune checkpoint inhibitors (ICI) in non-selected prostate cancer patients opposed to the overall landscape of negative trials for immunotherapy, including the KEYNOTE-641 and KEYNOTE-991 studies as presented at the ESMO Congress 2023. “The CONTACT-02 trial results may present the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC progressing on first-line ARPI”, explains Dr Christoph Oing, Northern Centre of Cancer Care, The Freeman Hospital, Newcastle upon Tyne, United Kingdom. However, some caution is needed when interpreting the results from the CONTACT-02, according to Oing: “It is well established that a switch to a second ARPI in ARPI-resistant mCRPC has only limited activity and cannot be considered a standard of care anymore. Further, the median PFS improvement is so far only 2 months, whereas other clinically relevant secondary endpoints, such as median time to symptomatic skeletal-related events, median time to pain progression and the PSA response rates were similar in both arms. Notably, treatment-related adverse events (TRAEs) were much more prominent in the experimental arm with 90% of any grade TRAEs and 33% ≥ grade 3 TRAEs, which led to treatment interruption and discontinuation in 63% and 13% of patients, respectively.”
In the study, OS data were still immature, but a trend toward OS improvement was observed in the group treated with the TKI and ICI combination compared to the control group (16.7 months vs 14.6 months; HR: 0.79; 95% CI: 0.58–1.07; p=0.13). “While we wait for the OS data to mature, it remains to be defined which patients derive substantial benefit from IO combination therapies where there would be a reason to accept higher toxicity. The CONTACT-02 results so far do not represent a breakthrough to implement immunotherapy into the mCRPC treatment landscape”, concludes Oing.