Agarwal Shares Insight on Promise With Cabozantinib/Atezolizumab in mCRPC

Neeraj Agarwal, MD

The combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) demonstrated exciting clinical activity and a tolerable safety profile in patients with metastatic castration-resistant prostate cancer (mCRPC) in cohort 6 of the phase Ib COSMIC-021 trial (NCT03170960), according to Neeraj Agarwal, MD, adding that a phase III trial is planned to explore the combination in a larger group of patients.

“The [fact that we saw] very exciting overall objective responses and duration of responses, [a good] disease control rate, and such high tolerability with this regimen [in this patient population] makes it very, very promising,” said Agarwal, who is lead study author of COSMIC-021.

Among 44 patients with mCRPC, the combination induced an objective response rate (ORR) of 32% (80% CI, 23-42) at a median follow-up of 12.6 months (range, 5-20), according to findings of this COSMIC-021 cohort that were presented at the 2020 Genitourinary Cancers Symposium.

Moreover, 48% (n = 21) of patients had stable disease, 4.5% (n = 2) had a confirmed complete response, and 27% (n = 12) had a confirmed partial response. Additionally, 18% (n = 8) of patients experienced disease progression and 2.3% (n = 1) were missing data.

Notably, among 36 patients with high-risk clinical features, such as visceral and/or extra-pelvic lymph node metastases, the ORR was 33%.

The median duration of response (DOR) was 8.3 months (range, 2.8-9.8+) and the median time to objective response was 1.6 months (range, 1-7). The disease control rate (DCR) among all patients was 80% (n = 35), and 32% (n = 14) of patients remained on treatment at the data cutoff.

No new safety signals were observed, said Agarwal. Treatment-related grade 3/4 adverse events (AEs) occurred in 59% (n = 26) of patients. Among the most commonly reported grade 3 events were fatigue, diarrhea, and hyponatremia (6.8% each).

Immune-related grade 3 AEs were observed in 9.1% (n = 4) of patients, and included increased alanine aminotransferase levels (4.5%), as well as adrenal insufficiency, increased aspartate aminotransferase levels, immune-mediated hepatitis, and increased lipase levels (2.3% each).

“I'm looking forward to the results from all 130 patients in this trial,” said Agarwal. “Hopefully, our patients will have the option of going on the phase III trial, which will be activating soon and will be available in various centers across the United States and across the globe.”

In an interview with OncLive^® during the 2020 Genitourinary Cancers Symposium, Agarwal, director of the Genitourinary Oncology Program, professor of medicine, physician, and investigator at Huntsman Cancer Institute at the University of Utah, discussed the COSMIC-021 trial and shared the next steps for this research.

OncLive: Could you provide some background to the COSMIC-021 trial?

Agarwal: COSMIC-021 began as a multi-cohort, phase I trial evaluating the early efficacy and safety of cabozantinib with atezolizumab in multiple tumor types. Cabozantinib is TKI, and we knew based on laboratory and preclinical data, that [the agent could] have [potential] synergy with a PD-L1 inhibitor, which is atezolizumab in this context.

The study started in patients with mCRPC; we had a 30-patient cohort. After [we saw] the efficacy data [with the combination], we expanded the cohort to 130 patients. Also, a phase III trial is already being planned.

For entry on the [phase Ib] study, patients were required to have mCRPC and progressive measurable disease. Almost half of the patients had received both abiraterone acetate (Zytiga) and enzalutamide (Xtandi). One-third of patients had received prior docetaxel in the castration-sensitive prostate cancer setting.

We saw responses that have never been seen thus far with any immunotherapy combination, or, for that matter, with any combinatorial regimen in this prostate cancer setting. Please note that the median overall survival in this patient population is [usually] around 15 months. This is a population with a very high unmet need, and we saw an ORR of 32%. An additional 48% of patients had stable disease, which equates to an 80% DCR. More remarkably, the responses were durable. The median DOR was around 8 months.

[Considering all of this], we are seeing very exciting outcomes. More importantly, we did not observe any new safety signals. Cabozantinib with atezolizumab are both approved for [use in] various other disease settings and [when the agents were used in combination, they] did not result in any new safety signals. In fact, most of the AEs were grade 1/2; there were rare grade 3 [AEs] and literally no grade 4 AEs. [This was all reported in] a population that is much older than many other patient populations with other kinds of cancers.

What do you hope to see with longer follow-up?

Obviously, 100% of patients are not responding [to this combination]. Why are 32% of patients responding, and why are only 47% of patients achieving stable disease as a best response? We would like to see everyone responding [to this treatment]. That is a challenge across oncology; that is not unique to prostate cancer. I believe finding biomarkers of response is very important; it's equally important to know who is not going to respond to this treatment. Also, can we do something else, in addition to the combination, to improve their response rates?

These are all challenges. What we are going to do to circumvent these challenges? We are already collecting [blood or tissue biopsy] samples from the patients [who progressed on treatment].

As we move forward with the larger trial, 3 additional cohorts are testing the individual treatment with cabozantinib and atezolizumab alone and in combination. When patients experience disease progression on cabozantinib alone, they are basically being crossed over to the combination therapy arm. [Upon progression], they're having biopsies done or they’re having blood samples taken, and I believe we'll [eventually] have many samples available [that will shed some light on] why some patients are not responding [to the treatment] or why others are responding so well.

If this regimen is approved down the line, where could it fit best in the treatment paradigm?

If the combination is successful, we will not be selecting patients [for treatment] based on a biomarker. We are basically [considering this regimen for] patients who are progressing on novel hormonal therapy and who have measurable disease, which is not uncommon. I'm hoping that we'll see a benefit across the board and this regimen will be available to all of my patients.

Is there anything that you would like to add?

The phase III trial will start soon, and it will be available across the United States and in many countries across the globe. I'm really hoping that patients will have access to this clinical trial [that is examining] such an exciting and promising combination.

Agarwal N, Loriot Y, McGregor A, 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). bit.ly/2udnVFs.