Cabozantinib Plus Atezolizumab Improves PFS in Metastatic CRPC

In patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease progressed on a novel hormonal therapy, the combination of cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) improved radiographic progression-free survival (PFS) over a switch to a second hormonal agent, according to findings from a phase III trial presented at this year’s Genitourinary Cancers Symposium.

In this exclusive MedPage Today video, Neeraj Agarwal, MD, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City, discusses the results of the CONTACT-02 trial.

Following is a transcript of his remarks:

CONTACT-02 is a phase III trial in patients with metastatic castrate-resistant prostate cancer who had prior disease progression on a novel hormonal therapy or an androgen receptor pathway inhibitor, and who had to have extrapelvic soft tissue metastasis, either visceral metastasis or lymph node metastasis.

The dual primary endpoints were progression-free survival and overall survival. The progression-free survival was assessed by blinded independent radiology review only on soft tissue metastasis as measured by RECIST [Response Evaluation Criteria in Solid Tumors] 1.1. And this is an important thing to remember, which differentiates this trial from almost all trials which have been reported in the metastatic CRPC setting.

We also measured PFS in patients who had bone metastasis by PCWG3 [Prostate Cancer Clinical Trials Working Group 3], and I’ll elaborate on that later in a second. And as I said, overall survival was another primary endpoint.

The patients were randomized to cabozantinib plus atezolizumab versus second NHT [non-hormonal therapy]. So if they got abiraterone [Zytiga], they got enzalutamide [Xtandi] as a second NHT.

The median progression-free survival was significantly improved, with a 35% reduction in risk of progression or death. The hazard ratio was 0.65 for PFS favoring cabozantinib plus atezolizumab. The overall survival data [were] immature, at 49% maturity, but hazard ratio is 0.79, which favor cabo/atezo at the moment, and we look forward to presenting the overall survival data later this year.

If you look at the subgroups, PFS seemed to benefit patients across the subgroups. And if you look at the subgroups of clinical interests such as patients with liver metastasis, patients who received docetaxel chemotherapy in the hormone-sensitive setting, which was allowed, the magnitude of benefit was even higher.

There was a 57% reduction in risk of progression or death in patients with liver metastasis with cabo/atezo, [and] a 43% reduction in risk of progression or death in patients who received prior docetaxel chemotherapy in the hormone-sensitive setting. Even in patients with bone metastasis, there was a 33% reduction in risk of progression or death.

If you look at the side effects of the agent, there were more grade 3/4 side effects in the cabo/atezo arm, as we would expect, as these combinations of TKI [tyrosine kinase inhibitor]/IO [immuno-oncology] are approved and widely available and used in the community. So there were 48% grade 3/4 side effects versus 23% grade 3/4 side effects in the second NHT arm. But if we look at the most common grade 3/4 side effects, there was hypertension in 7%, anemia in 6%, which was actually less than the control arm, fatigue and diarrhea in 4%. And we know these side effects are known, well established, and we know how to manage them very well.

If we look at other clinically meaningful endpoints, time to chemotherapy, time to symptomatic skeletal events, they seem to favor cabo/atezo over second NHT. If you look at time to deterioration in quality of life as reported by the patients, there was no difference in both arms, which suggests that cabo plus atezolizumab did not adversely affect quality of life relative to the second NHT, despite the fact that we were using two drugs versus one drug.

And lastly, I would like to highlight, based on the questions on the control arm, that almost all patients, or almost all trials with metastatic CRPC currently are enrolling with second NHT as a control arm. So almost all recently reported trials such as PSMAfore, VISION, SPLASH trial with the lutetium-177, or ongoing trials, they have second NHT as the control arm. And the reason for including second NHT as the control arm over docetaxel chemotherapy is, there has not been a single prospective randomized controlled trial showing the superiority of docetaxel over NHT after failure of one NHT.

Number two, patient preference and acceptance for chemotherapy is low in the U.S. and across the world, with about one-third of patients receiving docetaxel chemotherapy during their entire lifespan living with metastatic prostate cancer.

And lastly, based on the recent trials where NHT and chemotherapy were control arms in respective trials of pembrolizumab [Keytruda] plus enzalutamide versus enzalutamide, for example, or pembrolizumab plus docetaxel versus docetaxel after mCRPC progressed on NHT, the median PFS with enzalutamide at 9 months, and median PFS with docetaxel at 8.3 months, seemed to be very similar.

So I think we, based on all these data and based on our discussion with regulatory authorities, we think NHT control arm is an appropriate arm in these trials.

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