Dr. Agarwal on data from the phase 3 CONTACT-2 trial in mCRPC

Commentary
Video

“If you put everything together, the cabo/atezo combination statistically significantly improved the progression-free survival and reduced the risk of progression or death by 35% in a patient population with very poor prognosis,” says Neeraj Agarwal, MD, FACSO.

In this video, Neeraj Agarwal, MD, FASCO, shares findings from the CONTACT-2 trial (NCT04446117), a phase 3 trial that included patients with metastatic castrate resistant prostate cancer who had experienced disease progression on a novel hormonal therapy or androgen receptor pathway inhibitor and who had extra pelvic soft tissue metastasis. Patients were randomly assigned to receive cabozantinib, a TKI, plus atezolizumab, an immune checkpoint inhibitor, vs an alternate novel hormonal therapy. The dual primary end points were progression-free survival (PFS) and overall survival (OS). Agarwal is a professor of medicine and the director of the genitourinary oncology program at the Huntsman Cancer Institute at the University of Utah in Salt Lake City, Utah.

Video Transcript:

We presented the results on the PFS primary end point. Overall survival is still immature with 49% maturity. PFS was improved significantly with cabo/atezo over NHT with a 35% reduction in risk of progression or death with a hazard ratio of 0.65 [and] with a p-value of 0.007. The trial met the primary end point.

Interestingly, if you look at the clinical subgroups of interest, so if you look at the subgroup analysis for the PFS I showed, PFS was improved across the subgroups. I'd like to highlight some of the subgroups of clinical interest for our viewers because this trial recruited patients with measurable soft tissue metastasis and primary PFS end point was based on RESIST 1.1 immeasurable soft tissue lesions. Although another end point was PFS assessed by PCWG3, including patients with bone metastasis That was very consistently improved in a very similar fashion with a hazard ratio of 0.62. There was no ambiguity that PFS was improved in all patients. But then if you look at the clinical subgroup of interest, which is patients with visceral metastasis–40% patients in each arm had visceral metastasis and a quarter of patients had liver metastasis, so quite a poor prognosis patient population–the hazard ratio for PFS in patients with liver metastasis was 0.43. It's a 57% reduction in the risk of progression or death with cabo/atezo vs alternate NHT, which is quite remarkable in my view. There was a tripling of PFS benefit with cabo/atezo.

Then you look at patients who received prior docetaxel chemotherapy in the castration-sensitive setting, it was a hazard ratio of 0.57. So, 43% reduction in the risk of progression or death with cabo/atezo, with doubling of PFS with cabo/atezo. Even in the bone metastasis population, there was a 33% reduction in risk of progression or death with cabo/atezo. So, overall, all the clinical pre-specified subgroups of clinical interest seem to be benefiting. The overall survival data, as I said, are immature with 49% maturity, but hazard ratio is 0.79. So, the trend favors cabo/atezo. We hope to see overall survival benefit in the near future. But as long as the trends are not opposite, if overall survival is trending and right direction, I think this is very good news overall for the combination.

If you look at the side effects, we didn't see any new safety signals. TKI/IO combinations are widely used in the community. As we know cabo/nivo combination is approved for metastatic RCC, and it is a quite often used combination. We also know there are other TKI/IO combinations that are approved out there for multiple cancer types. We have pretty good experience on how to manage the side effects of these widely available combinations. So, if you look at the grade 3/4 side effects [with the] cabo/atezo arm, 7% of patients with hypertension, 6% of patients with anemia grade 3/4, which was actually slightly lower than the control arm. We think this is because of disease, not because of the drug. Then diarrhea and fatigue in 4% [of patients]. So, overall, the side effect profile seems to be pretty well manageable. There is quite a lot of experience in managing side effects of the TKIs.

Regarding other clinical secondary end points, time to chemotherapy, time to symptomatic skeletal event, [they] seem to favor cabo/atezo. There was no deterioration in quality of life as reported by the patients in cabo/atezo relative to the control NHT arm. The time to deterioration and quality of life was quite similar. We don't think cabo/atezo is adversely impacting quality of life relative to the control arm. Remember, these patients must have had received an NHT as a first-line therapy, and the median progression-free survival on the first NHT was 12 months in both arms. So, these patients were quite responsive and tolerant to the NHT class before entering the trial. Because of that, dual drugs are not actually adversely impacting quality of life compared to another NHT; it's quite remarkable in my view. If you put everything together, the cabo/atezo combination statistically significantly improved the progression-free survival and reduced the risk of progression or death by 35% in a patient population with very poor prognosis. If you look at the overall survival of the control arm that is 14.6 months, and that is mostly driven by a high number of patients with visceral metastasis, at 40%, liver metastasis at 25%. So, [this is a] high-risk patient population. We know that the use of chemotherapy is quite low across the board. In this patient population with a high unmet need, cabo/atezo combination improves PFS in a meaningful fashion, and I'm hoping that we have this combination available in the community for our patients in the near future.

This transcription has been edited for clarity.

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