Cabozantinib and atezolizumab show more efficacy compared to second NHT in patients with mCRPC

Prof Neeraj Agarwal - University of Utah, Salt Lake City, USA

The CONTACT-2 study is a phase III randomised trial which recruited patients with metastatic castrate resistant prostate cancer after prior disease progression on a novel hormonal therapy or an androgen receptor pathway inhibitor such as abiraterone or enzalutamide. They were randomised to the novel combination of cabozantinib, a tyrosine kinase inhibitor already approved for several other cancers, plus atezolizumab, an immune checkpoint inhibitor. So cabozantinib/atezolizumab versus the second NHT arm, so the NHT which was not used before. The dual primary endpoints were progression free survival and overall survival.

I would like to highlight, or bring your attention to, the PFS endpoint. The study population had to have extrapelvic measurable disease when they had metastatic CRPC with prior treatment with a novel hormonal therapy. So extrapelvic soft tissue metastasis had to have been measurable and the PFS endpoint was based on RECIST 1.1 on soft tissue measurable disease. However, because prostate cancer patients have bone metastasis as very common, we had another key endpoint looking at PFS by PCWG3 in patients with bone metastasis.

So we had a very comprehensive evaluation of PFS and then overall survival was another endpoint which is immature at this point of time, as I will mention in a second. Now, key stratification factors were liver metastasis, prior receipt of docetaxel chemotherapy in the castration sensitive setting, and receipt of novel hormonal therapy either in the castration sensitive setting or the castration resistant prostate cancer setting.

The dual primary endpoints, as I said, were PFS and OS. PFS was met, as I said. I want to re-emphasise that the trial met the primary endpoint of progression free survival favouring cabozantinib and atezolizumab. There was a 35% reduction in risk of progression or death with a p-value of 0.0007. If we look at the PFS in clinically relevant subgroups, so, first of all, PFS was improved across the subgroups, it did not really change based on prior therapy or age of the patient or where patients were recruited. But if we look at subgroups of clinical interest, such as patients with liver metastasis, patients with prior docetaxel chemotherapy in the castration sensitive setting, or patients with bone metastasis, cabozantinib/atezolizumab improved PFS consistently in all these subgroups. The best part is the benefit was highest in patients with the poorest prognosis, which is patients with liver metastasis.

So before I talk about that, I would like to mention that 40% of patients in this study had visceral metastasis, which is double what we see with the usual mCRPC trial. Up to a quarter of patients had liver metastasis. So in liver metastasis patients there was a 57% reduction in the risk of progression or death and a doubling of PFS with cabozantinib/ atezolizumab. If we look at patients with prior docetaxel chemotherapy there was a 43% reduction in the risk of progression or death with a doubling of PFS. Even in bone metastasis patients there was a 33% reduction in the risk of progression or death. So the benefit was very consistent.

Now, coming to overall survival, data are immature, it’s a 49% maturity, but the trend favours cabozantinib/atezolizumab with a hazard ratio of 0.79. The overall survival in the control arm, I’d like to bring your attention to this fact, is 14.6 months. The control arm overall survival is 14.6 months and that basically tells us this is not a newly diagnosed metastatic prostate cancer patient population who is expected to live for many, many years. This is the population of highest unmet need where we need to do something. The overall survival is even inferior or poor in patients with liver metastasis or visceral metastasis. So in this context, just to put things in perspective, glioblastoma has this overall survival of 14.6 months. So if we are reducing the PFS by 35%, there’s a 35% reduction in risk of PFS and death, these are very meaningful data for our patients.

Now, I’d like to mention briefly the side effect profile. We did not see any new safety signal. Cabozantinib is already a widely available, widely used drug in the community, especially also in the combination with the checkpoint inhibitor nivolumab. It’s already approved in the metastatic RCC setting and we did not see any new side effects although, yes, grade 3/4 side effects are more common. But this patient population with the NHT control arm, they had to have NHT before and the median progression free survival on the first NHT was 12 months. So this patient population was quite tolerant and responsive to NHT control. Especially with that in mind, with two drugs we didn’t see any new safety signal. The most common grade 3/4 side effects were hypertension in 7%, diarrhoea and fatigue in 4% each. So overall quite manageable side effects. We are very familiar as far as managing these side effects are concerned.

Now, the last thing, the clinically relevant secondary endpoints – time to chemotherapy, time to symptomatic skeletal event – they seemed to favour cabozantinib/atezolizumab as well. There was no excessive deterioration in quality of life with cabozantinib/atezolizumab versus NHT despite two drugs being compared to one drug. So the time to deterioration in quality of life as reported by patients was similar in both arms suggesting that cabozantinib/atezolizumab did not impact adversely quality of life relative to the second NHT.

So overall my final conclusion on our CONTACT-2 data is that the combination of cabozantinib plus atezolizumab significantly improves progression free survival and meets the primary endpoint in this patient population of mCRPC with prior NHT with high risk disease. This is a patient population with high unmet need and we are very excited about the potential of this combination to be approved in our clinic in the near future.

Please can you elaborate on the control arm discussed during your presentation?

Yes, people have questioned about why we used NHT and not docetaxel chemotherapy in the control arm. My answer is we have to have a control arm which is acceptable to patients. Historically, at least in the US, the use of docetaxel in the castration resistant prostate cancer setting has been around one-third of the patients despite docetaxel being approved in this setting for two decades now.

If we look at metastatic castration sensitive prostate cancer where patients are much healthier, docetaxel has consistently been used in the real world setting in less than 10% of patients, despite one year improved survival in the CHAARTED study in metastatic hormone sensitive prostate cancer.

So the number one reason is docetaxel is not acceptable based on all the data we have to a large number of patients. Second, which is more important, docetaxel has never been compared with a novel hormonal therapy. After failure of one NHT there has not been a single randomised trial showing that docetaxel is superior to the NHT.

Now, let’s talk about recently reported trials which indirectly compared the efficacy of docetaxel and NHT in this patient population. So if we look at, say, the KEYNOTE-921 trial which compared pembrolizumab plus docetaxel versus docetaxel in metastatic CRPC after prior therapy with NHT, and the KEYNOTE-641 trial which compared pembrolizumab plus enzalutamide versus enzalutamide in mCRPC with prior treatment with NHT. So a very similar patient population, they all have received prior NHT, now progressing on that. If you look at the absolute PFS on enzalutamide that is 9 months and if you look at absolute PFS in docetaxel in different trials it’s 8.3 months. So where is the evidence that docetaxel is better than NHT? Anywhere? We look at real world data – we have published propensity match analysis – we have not found evidence yet that docetaxel is superior to NHT.

So if we combine these two factors together, that it is unacceptable to the majority of patients and then it is not showing better survival than NHT, we didn’t think it was appropriate or it was possible to complete a trial in a timely fashion if you have a docetaxel control. Can you imagine, this trial recruited patients in the middle of the COVID pandemic and if we had a docetaxel therapy arm without any evidence that it is superior to NHT, would we ever have completed this trial?

So the bottom line, this is what we have. We think we have done a very strong, well-conducted trial. We have solid data from the trial in this patient population with highest unmet need and I'm really hoping that we have this combination approved and available in our clinic for our patients in the near future.

What is next for this study?

We will be following, looking for overall survival, for example, that is still immature. Regardless of overall survival, as we see, most of the early mCRPC studies have not shown overall survival but if we see that it will be great, if we don’t we still think the combination should be approved based on quite strong data in the highest risk patient population in this study.

Then we’ll obviously be looking at who are responding for a long time – there are some patients who have responded really well – versus who did not respond. So go back and look at the biology of those tumours to see why they didn’t respond or why they responded and look for biomarkers of efficacy or lack of efficacy.

Will you be looking for other studies with different control arms?

We will be using docetaxel therapy as a control if we think it is a valid option in a given patient population. So if we were to recruit a patient population with symptomatic prostate cancer where docetaxel is approved really, yes, docetaxel should be a control arm. But if we are recruiting a patient population with relatively asymptomatic prostate cancer where most of the patients are really going on the study based on PSA rise, we cannot really justify giving docetaxel to them. I doubt patients will be willing to accept docetaxel chemotherapy if they have no symptoms because of disease. So a great question, the answer is it depends upon the situation.