Cabozantinib plus atezolizumab in metastatic prostate cancer (CONTACT-02): final analyses from a phase 3, open-label, randomised trial.

backgroundPatients with metastatic castration-resistant prostate cancer (mCRPC) with extrapelvic soft-tissue metastases that has progressed on an androgen receptor pathway inhibitor (ARPI) have a poor prognosis with few treatment options. We aimed to assess efficacy and safety of cabozantinib, a tyrosine kinase inhibitor with immunomodulatory properties, plus the PD-L1 inhibitor atezolizumab in these patients.

methodsCONTACT-02 is an open-label, randomised, phase 3 study that enrolled patients at 184 sites across 24 countries (in Europe, North America, Asia-Pacific, and Latin America). Men aged 18 years and older, with an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who had mCRPC and measurable extrapelvic soft-tissue metastases (lymph node or visceral) that had progressed on one previous ARPI were eligible. Patients were randomly assigned 1:1 to cabozantinib (40 mg orally once daily) plus atezolizumab (1200 mg intravenously once every 3 weeks) or ARPI switch (abiraterone 1000 mg orally once-daily plus prednisone 5 mg orally twice-daily, or enzalutamide 160 mg orally once-daily) using a web-based interactive response technology system and stratified by the presence of liver metastasis, previous docetaxel therapy, and disease status at first ARPI initiation. Dual primary endpoints were progression-free survival in the first 400 randomly assigned patients (progression-free survival intention-to treat [ITT] population) and overall survival in all randomly assigned patients (ITT population). Safety was assessed in all patients who received at least one dose of study treatment. Although the study is ongoing, with some patients remaining in follow-up, this analysis represents the protocol-specified final analysis. This trial is registered with ClinicalTrials.gov, NCT04446117.

findingsBetween Aug 20, 2020 and June 7, 2023, 575 patients were randomly assigned to cabozantinib plus atezolizumab (n=289) or ARPI switch (n=286). Most patients were White (440 [77%]) or Asian (78 [14%]). After a median follow-up of 11·8 months (IQR 9·9-19·3), cabozantinib plus atezolizumab significantly improved progression-free survival versus ARPI switch (median 6·3 months [95% CI 6·2-8·8] vs 4·2 months [3·7-5·7]; hazard ratio [HR] 0·65 [95% CI 0·50-0·84], p=0·0007). After a median follow-up of 23·1 months (IQR 17·4-30·5), overall survival was not significantly different between the cabozantinib plus atezolizumab and ARPI switch groups (median 14·8 months [95% CI 13·4-16·7] vs 15·0 months [13·0-18·5]; HR 0·89 [95% CI 0·72-1·10], p=0·30). Any-cause grade 3-4 adverse events occurred in 158 (56%) of 284 patients given cabozantinib plus atezolizumab and 74 (26%) of 284 patients given ARPI switch; the most common in the cabozantinib plus atezolizumab group were hypertension (24 [8%] of 284 patients) and anaemia (23 [8%]) and the most common in the ARPI switch group was anaemia (18 [6%] of 284 patients). Serious adverse events deemed related to treatment occurred in 45 (16%) of 284 patients in the cabozantinib plus atezolizumab group and in 11 (4%) of 284 patients in the ARPI switch group; the most common with cabozantinib plus atezolizumab was diarrhoea (five [2%] of 284 patients) and the most common with ARPI switch was increase in alanine aminotransferase (two [1%] of 284 patients). Adverse events of any cause led to discontinuation of all components of study treatment in 49 (17%) of 284 patients in the cabozantinib plus atezolizumab group and in 42 (15%) of 284 patients in the ARPI switch group. No treatment-related deaths occurred.

interpretationCabozantinib plus atezolizumab, a novel drug combination that does not directly target androgen receptor signalling, could be a useful treatment option for patients with mCRPC and soft-tissue metastases who have progressed on an ARPI.

fundingExelixis in partnership with Ipsen, Takeda, and Roche.