The combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) continued to show clinically meaningful activity in previously treated patients with locally advanced or metastatic castration-resistant prostate cancer (mCRPC), including those with high-risk clinical features, according to updated data from the phase 1b COSMIC-021 trial.1
The updated data included 132 patients, all of whom had prior enzalutamide (Xtandi) and/or abiraterone acetate (Zytiga), and 101 of whom had high-risk disease. The investigator-assessed objective response rate (ORR) in high-risk patients was 27%, comprising a 2% complete response (CR) rate and a 25% partial response (PR) rate. Per the assessment of the Blinded Independent Radiology Committee (BIRC), the ORR was 18%, comprising all PRs.
“These results from cohort 6 of COSMIC-021 suggest cabozantinib in combination with atezolizumab holds promise as a potential new treatment option in metastatic castration-resistant prostate cancer, a difficult-to-treat tumor type that typically has a poor prognosis,” Neeraj Agarwal, MD, professor of Medicine, Huntsman Cancer Institute, University of Utah, and an investigator on the trial, stated in a press release.
The multicenter, open-label, phase Ib COSMIC-021 trial is evaluating the combination of the PD-L1 inhibitor atezolizumab and the multikinase inhibitor cabozantinib in patients with locally advanced or metastatic solid tumors. The mCRPC cohort is cohort 6 of the trial. Patients in this cohort were allowed to have received prior docetaxel for hormone-sensitive disease. The study design defined high-risk disease as “measurable visceral and/or extra-pelvic lymph node metastases.”1
The median follow-up time in the high-risk subgroup was 15.8 months. In these patients, the disease control rate was 88% per investigator assessment and 84% per the assessment of the BIRC. Data for progression-free survival and duration of response were reported to be comparable between the investigator and BIRC assessment; however, specific numbers for these endpoints have not yet been released.
There were no new safety signals that emerged in this updated, expanded cohort analysis as compared with the interim analysis. Overall, 12% of patients discontinued treatment due to adverse events unrelated to disease progression.
“There is a significant need for more options beyond chemotherapy once patients progress on androgen-deprivation therapy, so it is encouraging to see the response rates, disease control and tolerable safety profile associated with cabozantinib in combination with atezolizumab in this trial,” stated Agarwal.
Exelixis, the developer of cabozantinib, intends to present the full results of this analysis at a medical meeting in the second half of this year.
Data from the interim analysis, which included the first 44 enrolled patients in cohort 6, were shared during the 2020 ASCO Virtual Scientific Program.2 The combination elicited an ORR of 32% in these 44 patients. There were 3 CRs and 11 PRs. 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 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.
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.
The ongoing phase 3 randomized, open-label, CONTACT-02 study (NCT04446117) is exploring cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) versus second novel hormone therapy (NHT; abiraterone, enzalutamide, etc) in patients with mCRPC who previously received 1 NHT to treat metastatic castration-sensitive prostate cancer, non-metastatic CRPC, or mCRPC.
Primary outcomes measures are overall survival and progression-free survival, with ORR as a secondary outcome measure. The target enrollment is 580 patients, and there are 62 study locations for the trial in the United States and worldwide.
Click here to watch a video of Dr. Agarwal discussing the CONTACT-02 study.
1. Exelixis Announces Phase 1b Results from Cohort 6 of COSMIC-021 Trial in Patients with Metastatic Castration-Resistant Prostate Cancer. Published online May 24, 2021. Accessed May 24, 2021. https://bit.ly/3yytj2l.
2. 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.