Cabozantinib Plus Atezolizumab Prolongs Survival in mCRPC Subgroup

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Treatment with cabozantinib (Cabometyx) in combination with atezolizumab (Tecentriq) achieved a statistically significant improvement in progression-free survival (PFS), in patients with metastatic castration-resistant prostate cancer (mCRPC) and measurable soft tissue disease who have been previously treated with a novel hormonal therapy.¹

The combination also showed a trend toward overall survival (OS) improvement in this patient population, according to results from the interim analysis of the global phase 3 CONTACT-02 study (NCT04446117). OS data had not reached maturity at the time of the interim analysis and therefore, no statical significance was shown.

The safety profile of cabozantinib plus atezolizumab in the study was expected, based on prior safety data. Specifically, the label for cabozantinib warns that adverse events like diarrhea, fatigue, Palmar-plantar erythrodysesthesia (PPE), decreased appetite, hypertension, nausea, vomiting, weight decreased, constipation are common and occurred in more than 20% of patients treated with the agent in clinical trials. When added to an immune checkpoint inhibitor (ICI), nivolumab (Opdivo) common AEs include diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

The use of ICIs for the treatment of mCRPC has been studied considerably², including in the phase 3 KEYNOTE-199 study (NCT02787005) of pembrolizumab (Keytruda)³ and a phase 1 study of atezolizumab in patients with mCRPC who progressed on prior treatment of either enzalutamide (Zytiga) or sipuleucel-T (Provenge; NCT01375842).⁴ Based on these studies and others, however, single-agent ICI therapy does not work for all patients. Therefore, combining an ICI like atezolizumab with another mechanism. This was the rationale for the CONTACT-02 study, according to the investigators.²

CONTACT-02 is a phase 3, randomized, open-label, controlled study. Patients in the study are receiving 20-mg cabozantinib tablets given twice a day for a total dose of 40 mg in combination with IV atezolizumab 1200 mg/20 mL given once every 3 weeks or abiraterone acetate in 500-mg tablets once daily for a total daily dose of 1000 mg with Enzalutamide 160 mg once daily, and Prednisone 1000 mg once daily.⁵

In addition to the coprimary end points of PFS and OS, the study is exploring objective response rate per RECIST v1.1 by blinded independent review committee as its secondary end point.

Patients aged 18 years or older must have histologic or cytologic confirmation of mCRPC to enroll in addition to measurable disease per RECISTS v1.1, progressive disease, and ECOG performance score of 0 or 1, and adequate organ function, marrow function, and laboratory tests. All patients are required to be previously treated with either abiraterone, apalutamide (Erleada), darolutamide (Nubeqa), or enzalutamide and have undergone surgical or medical castration, with serum testosterone ≤ 50 ng/dL at the time of screening.

Patients are excluded from the study a prior nonhormonal therapy was initiated for the treatment of mCRPC, they received abiraterone within 1 week of study treatment, had radiation theory within 4 weeks or surgery within 4 weeks. Patients with known brain metastases, symptomatic or impending spinal cord compression or cauda equina syndrome or other comorbid conditions that may interfere with study treatment are also excluded from the study.

_REFERENCES:

_{1. Exelixis and Ipsen announce psitive results from phase 3 CONTACT-02 pivotal trial evaluating cabozantinib in combination with atezolizumab in metastatic castration-resistant prostate cancer. News release. Exelixis, Inc. August 21, 2023. Accessed August 21, 2023. https://ir.exelixis.com/news-releases/news-release-details/exelixis-and-ipsen-announce-positive-results-phase-3-contact-02}

_{2. Agarwal N, Azad A, Carles J, et al. A phase III, randomized, open-label study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy in patients with metastatic castration-resistant prostate cancer. Future Oncol. 2022;18(10):1185-1198.doi: 10.2217/fon-2021-1096. doi: 10.2217/fon-2021-1096}

_{3. De Bono JS, Goh JC, Ojmaa K, et al. KEYNOTE-199: Pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2018;36(suppl 15):5007. doi: 10.1200/JCO.2018.36.15_suppl.5007}

_{4. Petrylak DP, Loriot Y, Shaffer DR, et al. safety and clinical activity of atezolizumab in patients with metastatic castration-resistant prostate cancer: A phase I study. Clin Cancer Res. 2021; 15;27(12):3360-3369. doi: 10.1158/1078-0432.CCR-20-1981.}

_{5. Study of cabozantinib in combination with atezolizumab versus second NHT in subjects with mCRPC (CONTACT-02). ClincalTrials.gov. Updated Juky 17, 2023. Accessed August 21, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04446117}