Cabozantinib Plus Atezolizumab Shows Promise in mCRPC

Neeraj Agarwal, MD

The combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) showed clinically meaningful activity in patients with metastatic castration-resistant prostate cancer (mCRPC), including those with high-risk clinical features, according to findings from the phase 1b COSMIC-021 trial presented during the 2020 ASCO Virtual Scientific Program.

In a cohort of patients with mCRPC, the combination elicited an overall response rate (ORR) of 32%. Among 44 total patients, there were 3 complete responses and 11 partial responses. Twenty-one patients had stable disease, 8 patients had progressive disease, and data were not available for 1 patient. The disease control rate was 80%.

The median time to response was 1.6 months (range, 1-7) and the median duration of response was 8.3 months (range, 2.8-12.5+). Of note, the ORR was 33% in a subgroup of 36 patients with high-risk clinical features, which included those with visceral metastases and/or extra-pelvic lymph node metastases.

“The combination of cabozantinib and atezolizumab demonstrated a tolerable safety profile and clinically meaningful activity in men with mCRPC,” said lead study investigator Neeraj Agarwal, MD, professor, Huntsman Cancer Center, University of Utah. “[The mCRPC cohort] is being further expanded, and cohorts evaluating the contribution of cabozantinib and atezolizumab have been initiated. Further evaluation of cabozantinib and atezolizumab in mCRPC in a phase 3 trial is planned.”

Agarwal also noted that, “the combination treatment was associated with an increase in the number of activated cytotoxic T cells with concomitant decrease in immunosuppressive cells in peripheral blood.”

The multicenter, open-label, phase Ib COSMIC-021 trial is evaluating the combination of atezolizumab and cabozantinib in patients with locally advanced or metastatic solid tumors. Agarwal shared data for the first 44 patients enrolled in the mCRPC cohort. Prior treatment with docetaxel was permitted for those who had hormone-sensitive disease.

The median follow-up was 15.8 months (range, 9-23). Seventy-seven percent of the patients were white and 4.5% were black. Half of the patients had an ECOG performance status of 0 and the other half had a status of 1. Thirty-six (82%) patients had high-risk mCRPC, which was defined as having visceral and/or extra-pelvic lymph node metastases; 15 patients (34%) had visceral metastases and 27 (61%) had extra-pelvic lymph node metastases. Metastatic sites included lymph node (80%), bone (45%), lung (14%), liver (14%), adrenal gland (9%), and other (23%).

Twenty-five patients (57%) had a Gleason score ≥8 at diagnosis. Moreover, 12 patients (27%) received prior docetaxel for metastatic castration-sensitive disease, and all 44 patients had received prior novel hormonal therapy, including abiraterone acetate (Zytiga), enzalutamide (Xtandi), apalutamide (Erleada), or darolutamide (Nubeqa). The median time between most recent systemic therapy and enrollment was 1.3 months. Overall, 70% of patients had prior radiotherapy and 80% of patients had prior surgery for prostate cancer.

Cabozantinib was administered orally at 40 mg once daily and intravenous atezolizumab was given at 1200 mg every 3 weeks. The primary end point was ORR.

Regarding biomarkers, Agarwal said, “Preliminary data do not suggest an association between PD-L1 expression and antitumor activity.”

The rate of grade 3/4 adverse events (AEs) was 59%; treatment-related grade 3/4 AEs occurring in at least 5% of patients were fatigue (7%), diarrhea (7%) and hyponatremia (7%).

Immune-related grade 3/4 AEs occurred in 4 patients and AEs led to cabozantinib dose reductions in 19 patients. In 4 patients, there were AEs unrelated to disease progression leading to both cabozantinib and atezolizumab discontinuation. One treatment-related grade 5 AE of dehydration was reported in a 90-year-old patient with a 6-month history of heart failure.

Cabozantinib is currently indicated for the treatment of patients with advanced RCC, as well as for the treatment of patients with hepatocellular carcinoma (HCC) who received prior treatment with sorafenib (Nexavar). Atezolizumab has approved indications in urothelial carcinoma, lung cancer, metastatic triple-negative breast cancer, and HCC.

Agarwal N, Loriot Y, McGregor BA, et al. Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: Results of cohort 6 of the COSMIC-021 study. J Clin Oncol 38: 2020 (suppl; abstr 5564). doi: 10.1200/JCO.2020.38.15_suppl.5564.

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