CONTACT-02 Phase III Trial Findings on Cabozantinib-Atezolizumab Combination in mCRPC - Neeraj Agarwal

February 21, 2024

Alicia Morgans interviews Neeraj Agarwal about the CONTACT-02 trial, a phase III study that explores the combination of cabozantinib and atezolizumab in patients with metastatic castrate-resistant prostate cancer (mCRPC) who have progressed on one novel hormonal therapy (NHT). This trial, which focuses on patients with extrapelvic soft tissue metastasis, has shown a significant reduction in the risk of progression or death, marking the first phase III evidence of benefit from an immune approach in prostate cancer. The trial's rigorous methodology and the promising results, particularly in high-risk groups with liver metastasis, offer a beacon of hope for a patient population with limited treatment options. Dr. Agarwal's insights underline the importance of this combination therapy in potentially transforming clinical practice for patients with mCRPC, heralding a new era of treatment strategies that extend beyond traditional chemotherapy.


Neeraj Agarwal, MD, Professor, Presidential Endowed Chair of Cancer Research, Director GU Program, and the Center of Investigational Therapeutics (CIT) at the Huntsman Cancer Institute, University of Utah, Salt Lake City, UT

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

Read the Full Video Transcript

Alicia Morgans: Hi. I'm so excited to be here today with Professor Neeraj Agarwal, who is joining me from the Huntsman Cancer Institute at the University of Utah to talk about his really exciting oral presentation at GU ASCO 2024. Thank you so much for being here with me today.

Neeraj Agarwal: Thank you for having me. Always a pleasure.

Alicia Morgans: Wonderful. So tell me about this study, CONTACT-02. Tell me about the data that you were so fortunate to present, and you did a wonderful job, by the way.

Neeraj Agarwal: Thank you. That's very kind. So CONTACT-02 is a phase III trial utilizing a combination of cabozantinib plus atezolizumab, a TKI plus an immune checkpoint inhibitor, first to show benefit compared to a control NHT arm.

Just to step back, the COMET-1 trial, reported about seven, eight years ago, showed single-agent cabozantinib to have activity in patients with visceral metastasis, and even though the overall trial population did not meet the primary endpoint, we saw some activity in patients with more aggressive features like visceral metastasis or liver metastasis.

And then, fast-forward to 2020, '21, we did a trial of cabozantinib plus atezolizumab, which showed encouraging activity, which we presented at GU ASCO about three years ago. And based on this totality of data, we designed the CONTACT-02 trial combining cabozantinib plus atezolizumab in patients who had metastatic CRPC and who had disease progression on one NHT. And they had to have extrapelvic soft tissue metastasis. This was determined to be one of the required criteria based on the more encouraging signal we found with the combination in both previous trials.

So PFS and OS were the primary endpoints. And something unique about this trial was that PFS was assessed based on RECIST 1.1 only, including soft tissue measurable disease. So quite a strict measurement of PFS. However, we know that in the prostate cancer community, it is always interesting for us to see how the drug combination or any drug combination is doing in patients with bone metastasis.

We also had another endpoint of measuring PFS by PCWG3 in all patients who had bone metastasis. And the good news is both PFS are very consistent. So, coming back to the randomization or design, the trial randomized patients to these two arms, and randomization was stratified by the presence or absence of liver metastasis and prior docetaxel chemotherapy in the castration-sensitive setting.

So now let's look at the endpoints, the PFS and OS. So at the time of the data cutoff, or I would say 32% of patients were still on cabozantinib, atezolizumab. 24% of patients were on the control NHT arm. And it was an interim analysis for the OS, but the primary analysis for the PFS.

So the primary PFS analysis showed that there was a 35% reduction in the risk of progression or death with cabo-atezo in this trial compared to the NHT arm. Overall, the trial meets the primary endpoint. Overall PFS is statistically significant with cabo-atezo. But now I'd like to bring your attention to the subgroup of clinical interest, such as liver metastasis. So if you look at patients with liver metastasis or visceral metastasis, most treatments don't work, or work for a short time. So this is a patient population with a high unmet need.

So if you look at the patients with liver metastasis, the hazard ratio for benefit was 0.43. It was a 57% reduction in the risk of progression or death with cabozantinib, atezolizumab with a tripling of median PFS from two to six months. If you look at the bone metastasis prior docetaxel therapy patients, patients who had received docetaxel, the PFS was doubled with a 43% reduction in the risk of progression or death. Even in the bone metastasis population, there was a 33% reduction in the risk of progression or death with cabo-atezo.

So the overall message is that this combination seems to be helping pretty much all subgroups. We are not seeing one particular subgroup not benefiting from the cabo-atezo combination. Now, let's look at the overall survival. It is premature, immature at 49% maturity, but trends are supportive of cabo-atezo with a hazard ratio of 0.79.

Again, if we look at the subgroup analysis of liver metastasis, pre-docetaxel treated patients, and bone metastasis, very similar trends. So let's talk about the adverse events. As we know, cabo-atezo is a TKI immune checkpoint inhibitor combination, and we have several of these combinations available and approved for our patients for various cancers, at least in our context for metastatic kidney cancer for a long time now, two, three years now. And we know how to manage those side effects.

They're widely available, widely used combinations. So similar to what we know, what we have encountered in the clinic, the most common treatment-emergent side effects were, which were grade three and four, hypertension in 7% of patients. Anemia was one of the treatment-emergent side effects, but we think it is because of the disease because it was similar in both arms. And fatigue and diarrhea were present in 4% of patients each.

And we see these side effects, they're common side effects with most of the cancer therapies and especially with TKI-IO combination. And they were fairly treatable with dose reduction, dose hold and all that. And especially when you talk about dose reduction and dose modifications, they were quite common with the cabo-atezo combination. But if you really see how many patients discontinued cabo or atezo because of side effects, only 13% discontinued because of side effects. Again, reinforcing the belief that yes, we see these combinations with mostly TKIs, but we can manage them with dose reductions or temporary dose holds.

If you look at the median dose intensity of cabozantinib, that was 94% in the population. If you look at the median dose intensity of atezolizumab, it was 83% in the population. So basically, patients were able to tolerate the medication until they did not progress.

And then, the last thing is the clinically meaningful relevant endpoints such as time to chemotherapy, such as time to symptomatic skeletal event, they seem to favor cabo-atezo. So overall, as we have discussed, chemotherapy is not a very exciting option for our patients in a consistent fashion. And if you delay chemotherapy, that is meaningful to my patients.

Alicia Morgans: So thank you so much for going through that. And before we get into chemotherapy and that because it's a very complicated topic to your point for a patient and certainly in a clinical trial, I wonder if we could dig in a little bit to the subgroups. And also, I just want to acknowledge that this is the first phase III study that actually finds a benefit in terms of the progression-free survival related to an immune approach.

And certainly, we've got cabozantinib here affecting the microenvironment and atezolizumab as our IO. But this is really, I think, quite a novel approach. And although I guess the approach isn't necessarily novel given that we do have the IO, it's the first time we're seeing some benefit

Neeraj Agarwal: In prostate cancer.

Alicia Morgans: prostate cancer in a phase III. So congratulations to you and the team and certainly congratulations to the patients who I hope had some benefit through this study. Now just to dig in a little bit, it did look like in that subset of patients who had liver metastases, and certainly to the patients who also were treated with chemotherapy in the metastatic hormone-sensitive setting, there were substantially pronounced benefits in these two groups.

When I see these patients in practice, these are groups that tend to have a more aggressive disease biology, perhaps a poor prognosis, there may be drivers that are causing disease to occur in the liver, and certainly drivers that might be associated with high-volume de novo metastatic disease that might make this patient more likely in my practice to get chemotherapy in the hormone-sensitive setting. What are your thoughts on how this approach may be most beneficial in these high-risk patients? Because I think that was actually one of the more striking things about this presentation.

Neeraj Agarwal: Of course, we see this challenging situation all the time in our clinic where patients have low acceptance for chemotherapy, patients have disease progression on one NHT, and especially in most of the real-world studies, we have seen that NHT followed by NHT is the most common sequence, at least in the USA or anywhere it is available because that's what patients tend to prefer over chemotherapy.

Any option we have available in our clinic, any novel option, anything beyond what we have right now will be very welcome news for our patients, for us, that we will at least have one more treatment option available in our clinic. And then we can, obviously as clinicians, we can define who is the right population or who should be getting this therapy. Because obviously, somebody has an immune disorder, they're not going to get atezolizumab. Somebody has terrible, uncontrolled hypertension, obviously, we will not be using cabozantinib in those patients, but I think it'll be great to have this option available in our clinic for these patients.

And I'd just like to bring your attention to the median overall survival. We don't have the final data yet. These are interim OS. But if you look at the median OS of the control arm, 14.6 months from the start of randomization, I started looking at the median OS of similar disease types, like what is the median, which other cancer has a median overall survival of 14.6 months? And what was striking to me was to see that glioblastoma or GBM has a very similar survival, 14 months plus.

And that made me think that this is not a newly diagnosed metastatic prostate cancer population, which is supposed to live for years. This is a patient population with relatively nothing available for them. As we know, most patients don't want to endure. The patient preference for chemotherapy is quite low and I will come to that in a moment. But to have an option, to improve PFS or to decrease the risk of progression or death by 35% in this very poor-risk population is quite meaningful to me.

Alicia Morgans: I think that's absolutely true. And to your point and to some of the questions that were raised at ASCO GU, it was questioned why was this control arm chosen? And I think you've alluded to this several times relating to current practice patterns and the difficulty that patients have getting over the hurdle of accepting chemotherapy.

I think particularly when we're randomizing patients in a clinical trial, it's hard to flip a coin and say you'll get chemo or you'll get IO and an agent that really is a TKI targeting the microenvironment. These are very different things for a patient to think about and then consent to. But I wonder, as you and the team were putting this together, and certainly it was a whole team that put together this study, what were you thinking in terms of randomization and the possibility that chemotherapy could be considered potentially for that control arm?

Neeraj Agarwal: That's a great question. I was hoping that you would ask this question and allow me to address this concern. To begin with, there has not been a single randomized trial to date comparing docetaxel chemotherapy with an NHT after NHT failure. Not a single trial. So we don't really have the data to show that docetaxel chemotherapy is superior to novel hormonal therapy after failure of one novel hormonal therapy.

Then you go to the CARD trial, which was a later setting where patients had received chemotherapy with docetaxel and NHT, and cabazitaxel was chosen as the competitor arm, and the control arm was NHT. And one important aspect of the trial was that these patients had to have failed the first NHT within 12 months. It started with six months, but they expanded the criteria to 12 months. So the median PFS on the first NHT in the CARD trial was around eight months, on the first NHT.

So the deck was already stacked against the control arm here. And again, full credit to the investigators for designing this beautiful trial. We got great data in this patient population. But again, like any trial, there are nuances, there are different aspects of a trial. So in the CARD trial, cabazitaxel was overall superior to the control NHT. But if you look at the patients with visceral metastasis, the PFS hazard ratio was 0.79.

I was intrigued by those data when I was going through the literature and then when I look at our CONTACT-02 trial data, similar control arm, only that our patients had a median PFS of 12 months on the first NHT. So the patient population is quite tolerant and responsive to the NHT class in general. So those patients are now randomized to cabo-atezo versus control NHT and they show a hazard ratio, which found a hazard ratio of 0.43 in patients with liver metastasis, which has more aggressive biology than visceral metastasis in general.

So I feel, and the last thing, the most important thing, if you look at real-world studies, around one-third of patients receive chemotherapy for their entire metastatic castrate-resistant prostate cancer setting. If you look at the castration-sensitive setting, less than 10% of patients have received docetaxel chemotherapy since 2013 every year despite an absolute one-year survival benefit seen in the CHAARTED study.

All these put together, it would have been impossible to recruit on a trial, as you mentioned, if you say chemotherapy is the control arm. We don't think realistically patients would have chosen the trial where there are so drastically different options and where chemotherapy acceptability is so low when other alternatives are available.

Alicia Morgans: So thank you for that. I do think that it's important for us as investigators to really look into the design, to think about it critically, but also to recognize the feasibility of completing these large trials in the patient population where we are hoping to perform the work and find the answers.

And there can be challenges here that make things really complex. So thank you, and certainly thank the team for putting that together. So final words, what would your message be on the CONTACT-02 trial?

Neeraj Agarwal: First trial to show the benefit of a TKI plus an ICI combination, cabozantinib plus atezolizumab benefit in our patients with metastatic castrate-resistant prostate cancer after failure of one NHT. I'm really hoping this option is available in our clinic so that we can improve the number of options for our patients and benefit many of those patients who are going to benefit from this combination.

Alicia Morgans: Well, thank you so much for talking this through with me. I so appreciate your time, and I really do look forward to digging more into that data and thinking about those patients with liver metastasis and the patients with prior docetaxel, and certainly following up on the overall survival. I think there is so much for us to learn. And congratulations to you, the team, and thank you to the patients who participated in the CONTACT-02 trial. Thank you.

Neeraj Agarwal: Thank you very much.