Cabozantinib and Atezolizumab Combo Has Synergistic Activity in Metastatic CRPC

Neeraj Agarwal, MD

Neeraj Agarwal,MD

Combining cabozantinib (Cabometyx) and atezolizumab (Tecentriq) induced durable responses in men with metastatic castration-resistant prostate cancer (CRPC) who had soft tissue progression after prior hormonal therapy.¹

In an interim analysis of expansion cohort 6 of the COSMIC-021 phase Ib study, which included subjects with CRPC and radiological progression in the soft tissue following enzalutamide (Xtandi) and abiraterone (Zytiga), the objective response rate (ORR) in 44 patients who received the combination was 32% (80% CI, 23%-42%), which included 2 (4.5%) with complete responses and 12 (27%) with partial responses,¹said Neeraj Agarwal, MD, who presented the data at the 2020 Genitourinary Cancers Symposium. In addition to the 14 responses, 21 patients (48%) had stable disease, for a disease control rate of 80%.

No new safety signals were uncovered with the combination. Only 1 patient had a grade 5 treatment-related adverse event (TRAE), which was dehydration in a 90-year-old patient with a 6-month history of heart failure. The overall rate of grade 3/4 TRAEs was 59%.

As single agents, cabozantinib and atezolizumab demonstrated ORRs of 5% and 0%,^2,3respectively, in patients with metastatic CRPC. According to Agarwal, professor of Medicine at Huntsman Cancer Center of the University of Utah in Salt Lake City, “Cabozantinib promotes an immune-permissive environment that may enhance response to immune checkpoint inhibitors.”

The clinical activity with the combination as opposed to monotherapy “is clearly indicative of synergy between these 2 drugs rather than merely additive actions,” he said.

The only viable option known to improve overall survival (OS) and progression-free survival in patients with measurable disease or soft tissue metastases after novel hormonal therapy is taxane chemotherapy, said Agarwal. “This combination has the potential to allow a nonchemotherapy option for those patients who are progressing on these earlier therapies and have limited options to date,” he said.

He continued, “When patients progress to the metastatic CRPC state after abiraterone, enzalutamide, or even apalutamide [Erleada], the median OS is 15 months. I think this is the most challenging patient population.”

Results from the dose-expansion phase of COSMIC-021—a multicenter, open-label study—were reported here. Eligible patients had measurable disease per RECIST 1.1 and had radiographic progression in soft tissue after enzalutamide and/or abiraterone. No prior chemotherapy was allowed except for previous docetaxel for therapy of metastatic castration-sensitive prostate cancer. Patients received oral cabozantinib at 40 mg once daily and intravenous atezolizumab at 1200 mg every 3 weeks. The cabozantinib dosage could be reduced to 20 mg daily and then further to 20 mg every other day to manage adverse events (AEs). Atezolizumab infusions could be delayed to manage AEs.

Tumors were assessed by computed tomography/magnetic resonance imaging at screening, every 6 weeks for the first 12 months, and then every 12 weeks thereafter.

Thirty-six of the 44 patients (82%) had high-risk metastatic CRPC, defined as having visceral and/or extrapelvic lymph node metastases. Fifteen patients (34%) had visceral metastases and 27 (61%) had extrapelvic lymph node metastases. Twenty-five patients (57%) had a Gleason score ≥8 at diagnosis. Twelve patients (27%) received prior docetaxel for metastatic castration-sensitive prostate cancer and all 44 had received prior novel hormonal therapy, including abiraterone, enzalutamide, apalutamide, or darolutamide (Nubeqa).

Data cutoff for this interim analysis was December 20, 2019, with a median follow-up of 12.6 months (range, 5-20). The time to objective response (OR) was a median of 1.6 months (range, 1-7) and the median duration of OR was 8.3 months (range, 2.8-9.8+). Among the 36 patients with high-risk clinical features, the ORR was 33%.

“The duration of response is impressive. We’re talking about an oral pill and a PD-1—axis inhibitor combination leading to responses, and most of the responses were happening as early as 6 weeks,” said Agarwal.

Seventeen of 34 (50%) patients with postbaseline assessment of prostate-specific antigen (PSA) had a decrease in PSA level. In 12 patients with ORs with at least 1 postbaseline PSA assessment, 8 (67%) had a decrease in the level of PSA ≥50%.

Fourteen patients (32%) were on study treatment at the time of data cutoff. Median duration of exposure to study medications was 6.3 months (range, 1-18). The rate of immune-related grade 3/4 AEs was 9.1%. Seventeen patients (39%) had AEs leading to cabozantinib dose reductions. Three patients (6.8%) had AEs unrelated to disease progression that led to discontinuation of both cabozantinib and atezolizumab.

The only grade 3 immune-related AE that occurred in more than 1 patient was an increase in the level of alanine aminotransferase, which occurred at a rate of 4.5%.

The study cohort is being expanded to include 130 patients,⁴said Agarwal.

According to a press release from Exelixis, the company plans to file for accelerated approval for the combination in a metastatic CRPC indication as early as 2021 based on regulatory feedback from the FDA and if clinical data from the recently expanded existing cohort and added metastatic CRPC cohorts support the decision. A pivotal phase III trial of the cabozantinib/atezolizumab combination in metastatic CRPC is being developed.⁴

References

1. Agarwal N, Loriot Y, McGregor BA, et al. Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of cohort 6 of the COSMIC-021 study.J Clin Oncol. 2020;38(suppl 6; abstr 139). doi: 10.1200/JCO.2020.38.suppl_6.139.
2. Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial.J Clin Oncol. 2013;31(4):412-419. doi: 10.1200/JCO.2012.45.0494.
3. Kim JW, Shaffer DR, Massard C, et al. A phase Ia study of safety and clinical activity of atezolizumab (atezo) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).J Clin Oncol. 2018;36(suppl 6; abstr 187). doi: 10.1200/JCO.2018.36.6_suppl.187.
4. Exelixis announces encouraging results for cabozantinib in combination with atezolizumab in metastatic castration-resistant prostate cancer [news release]. Alamedia, California: Exelixis, Inc; February 10, 2020. bit.ly/39svmaM. Accessed February 14, 2020.