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Clinical Trial
. 2025 Jul;26(7):860-876.
doi: 10.1016/S1470-2045(25)00209-8. Epub 2025 Jun 13.

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

Neeraj Agarwal  1 , Arun A Azad  2 , Joan Carles  3 , Nobuaki Matsubara  4 , Stéphane Oudard  5 , Fred Saad  6 , Axel S Merseburger  7 , Andrey Soares  8 , Bradley A McGregor  9 , Bogdan Zurawski  10 , Marinos Tsiatas  11 , Scott North  12 , Igor Bondarenko  13 , Margarita Alfie  14 , Evangelos Bournakis  15 , Lorenzo Antonuzzo  16 , Lena Evilevitch  17 , Andrew Simmons  17 , Fong Wang  17 , Roberta Ferraldeschi  18 , Prachi Nandoskar  17 , Sumanta K Pal  19
Affiliations
Clinical Trial

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

Neeraj Agarwal et al. Lancet Oncol. 2025 Jul.

Abstract

Background: Patients 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.

Methods: CONTACT-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.

Findings: Between 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.

Interpretation: Cabozantinib 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.

Funding: Exelixis in partnership with Ipsen, Takeda, and Roche.

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Conflict of interest statement

Declaration of interests NA reports institutional research funding from Exelixis (for this manuscript); honorarium for consultancy from Exelixis; research funding to institution from Arvinas, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, CRISPR, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Immunomedics, Janssen, Lava, Merck, Nektar, Neoleukin, Novartis, Oric, Pfizer, Roche, Sanofi, Seattle Genetics, and Takeda; travel accommodations or expenses from Exelixis and Pfizer; and receipt of medical writing services from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, CRISPR Therapeutics, Eisai, Eli Lilly, Exelixis, Genentech, Gilead, Janssen, Merck, Nektar, Novartis, Oric, Pfizer, Roche, and Seattle Genetics. AAA reports institutional research funding from Exelixis (for this manuscript); consulting fees from Aculeus Therapeutics, Astellas, Janssen, and Novartis; data safety monitoring board participation for KEYNOTE-695; leadership roles as Chair of the Urologic Oncology Group (Clinical Oncology Society of Australia), Chair of the Translational Research Subcommittee, and participant in the Scientific Advisory Committee (ANZUP Cancer Trials Group); receipt of medical writing services from Astellas, Exelixis, and Pfizer; honoraria from Aculeus Therapeutics, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Ipsen, Janssen, Merck Serono, Merck Sharpe Dohme, Novartis, Noxopharm, Pfizer, Sanofi, Telix, and Tolmar; participation on a scientific advisory board for Amgen, Arvinas, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Ipsen, Janssen, Merck Serono, Merck Sharpe Dohme, Novartis, Noxopharm, Pfizer, Sanofi, Telix, and Tolmar; travel or accommodation expenses from Amgen, Astellas, Bayer, Hinova, Janssen, Merck Serono, Novartis, Pfizer, and Tolmar; and research funding from Aptevo Therapeutics (institutional), Astellas (investigator), Astellas (institutional), AstraZeneca (institutional), AstraZeneca (investigator), Bionomics (institutional), Bristol Myers Squibb (institutional), Eli Lilly (institutional), Exelixis (institutional), Gilead Sciences (institutional), GlaxoSmithKline (institutional), Hinova (institutional), Ipsen (institutional), Janssen (institutional), MedImmune (institutional), Merck Serono (investigator and institutional), Merck Sharpe Dohme (institutional), Novartis (institutional), Pfizer (institutional), Sanofi Aventis (institutional), and SYNthorx (institutional). JC reports institutional research funding from AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, Astellas Pharma, AstraZeneca, Aveo Pharmaceuticals, Bayer, Blueprint Medicines Corporation, BN Immunotherapeutics, Boehringer Ingelheim España, Bristol Myers Squibb, Clovis Oncology, Cougar Biotechnology, Deciphera Pharmaceuticals, Exelixis, F Hoffmann-La Roche, Genentech, GlaxoSmithKline, Incyte, Janssen-Cilag, Karyopharm Therapeutics, Laboratoires Leurquin Mediolanum, Eli Lilly, Medimmune, Millennium Pharmaceuticals, Nanobiotix, Novartis Farmacéutica, Pfizer, Puma Biotechnology, Sanofi-Aventis, SFJ Pharma, and Teva Pharma; consulting fees from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Exelixis, Ipsen, Johnson & Johnson, MSD Oncology, Novartis (Advanced Accelerator Applications), Pfizer, and Sanofi; honoraria from Astellas Pharma, Bayer, Johnson & Johnson, and Sanofi; payment for expert testimony from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Exelixis, Ipsen, Johnson & Johnson, MSD Oncology, Novartis (Advanced Accelerator Applications), Pfizer, and Sanofi; travel or accommodation expenses from AstraZeneca, Bayer, BMS, Ipsen, and Roche; receipt of medical writing services from Exelixis; and advisory board participation for Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Exelixis, Ipsen, Johnson & Johnson, MSD Oncology, Novartis (Advanced Accelerator Applications), Pfizer, and Sanofi. NM reports institutional research funding from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Chugai, Eisai, Eli Lilly, Exelixis (for this manuscript), Janssen, MSD, Pfizer, PRA Health Science, Roche, Seagen, Taiho, and Takeda; travel or accommodation expenses from Pfizer; and receipt of medical writing services from Exelixis. SO reports institutional research funding from Exelixis (for this manuscript), Ipsen, Janssen, and Sanofi; consulting fees from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Exelixis, Ipsen, Johnson & Johnson, MSD, Novartis (Advanced Accelerator Applications), Pfizer, and Sanofi; honoraria from Astellas, Amgen, Bayer, Ipsen, Johnson & Johnson, Novartis, and Sanofi; payment for expert testimony from Astellas, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Johnson & Johnson, MSD, Novartis (Advanced Accelerator Applications), Pfizer, and Sanofi; travel or accommodation expenses from AstraZeneca, Bayer, BMS, Ipsen, Johnson & Johnson, and Novartis (Advanced Accelerator Applications); receipt of medical writing services from Exelixis; and advisory board participation for Roche. FS reports institutional research funding from Astellas, AstraZeneca, Bayer, BMS, Exelixis (for this manuscript), Janssen, Merck, Novartis, Pfizer, and Sanofi; consulting fees from Astellas, AstraZeneca, Bayer, Janssen, Merck, Novartis, and Pfizer; honoraria from Astellas, AstraZeneca, Bayer, Janssen, Merck, Novartis, and Pfizer; and receipt of medical writing services from Exelixis. ASM reports research funding from Accord, Ambu, Amgen, Apogepha, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, EUSAPharma, Exelixis, Farco, Ferring, Ipsen, Hexal, Sandoz, MedUpdate, MSD, Merck Serono, Novartis, Janssen, Pfizer, Takeda, Recordati, and Roche; consulting fees from Astellas and Janssen; honoraria from Astellas, Ipsen, and Janssen; payment for expert testimony from Pfizer; travel or accommodation expenses from Astellas and Janssen; receipt of medical writing services from Exelixis; and advisory board participation for Astellas, Ipsen, and Janssen. ASo reports research funding from Exelixis (for this manuscript); consulting fees from AstraZeneca, Bayer, Janssen, MSD, Novartis, and Pfizer; honoraria from Janssen, Merck Serono, Novartis, and Pfizer; travel or accommodation expenses from Bayer, Janssen, Merck Serono, and Novartis; and receipt of medical writing services from Exelixis. BAM reports institutional research funding from Aveo, BMS, Exelixis, Gilead, and Pfizer; consulting fees from Arcus, Aveo, BMS, Daiichi, Eisai, Exelixis, Genmab, Gilead, Hexagon, Eli Lily, and Pfizer; travel or accommodation expenses from American Society of Clinical Oncology; and receipt of medical writing services from Exelixis. BZ reports contracts from AstraZeneca AB, Merck & Co, Gilead Sciences, Calliditas Therapeutics, Immunocore, Aveo Pharmaceuticals, Bayer, Bristol Myers Squibb, Exelixis, F Hoffmann-La Roche, GlaxoSmithKline, Janssen-Cilag, and Novartis; and receipt of medical writing services from Exelixis. MT reports institutional research funding from Exelixis (for this manuscript); grants or contracts from AstraZeneca, BMS, Exelixis, Immunomedics, Merck, MSD, Pfizer, Roche, and Seagen; consulting fees from Astellas, Bayer, Ipsen, Janssen, Merck, MSD, and Pfizer; honoraria from Ipsen, Janssen, Merck, and MSD; travel or accommodation expenses from Ipsen, Jansen, Merck, MSD, and Pfizer; and receipt of medical writing services from Exelixis. SN reports institutional research funding from Exelixis; honoraria from Astellas, AstraZeneca, Bayer, BMS, EMD Serono, Merck, Novartis, and Pfizer; travel or accommodation expenses from EMD Serono; and receipt of medical writing services from Exelixis. IB reports institutional research funding from Exelixis (for this manuscript); and receipt of medical writing services from Exelixis. MA reports institutional research funding from Exelixis (for this manuscript); and receipt of medical writing services from Exelixis. EB reports institutional research funding from Exelixis (for this manuscript); and receipt of medical writing services from Exelixis. LA reports institutional research funding from AstraZeneca, Exelixis, and Novartis; consulting fees from Amgen, Astellas, AstraZeneca, Bayer, BMS, Ipsen, Merk Serono, MSD, and Roche; honoraria from Amgen, Astellas, AstraZeneca, Bayer, BMS, Ipsen, Merck Serono, MSD, Novartis, and Roche; travel or accommodation expenses from AstraZeneca, Ipsen, Novartis, Merck and Serono; and receipt of medical writing services from Exelixis. LE reports they are an employee of Exelixis; stock ownership in Exelixis; and receipt of medical writing services from Exelixis. ASi reports they are an employee of Exelixis; stock ownership in Exelixis; and receipt of medical writing services from Exelixis. FW reports they were an employee of Exelixis (at the time of this study) and are a current employee of Pfizer; receipt of medical writing services from Exelixis; and travel or accommodation expenses from Pfizer. RF reports they are an employee of Roche; own stock in Roche; and receipt of medical writing services from Exelixis. PN reports they were an employee of Exelixis at the time of this study; stock ownership in Exelixis; and receipt of medical writing services from Exelixis. SKP reports institutional research funding from Exelixis (for this manuscript); honoraria from IntrinsiQ, MJH Life Sciences, and PeerView; travel or accommodation expenses from CRISPR Therapeutics, Exelixis, and Ipsen; receipt of medical writing services from Exelixis; and leadership roles (unpaid) for American Society of Clinical Oncology, Medical Oncology Association of Southern California, and SoCal GU.

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