Sawyers Explains Lessons Learned After Atezolizumab/Enzalutamide Falls Short in mCRPC

Charles L. Sawyers, MD

The combination of atezolizumab (Tecentriq) and enzalutamide (Xtandi) failed to demonstrate an improvement in overall survival (OS) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC), resulting in the termination of the phase 3 IMbassador250 trial.

Because the trial was conducted in patients with very late-stage disease it is possible that it may have been too late to reactivate an immune response, said Charles L. Sawyer, MD. However, other research efforts done at the University of Texas MD Cancer Center have suggested that administering immunotherapy to these patients at diagnosis, prior to surgery, could improve the chance of cure following the procedure, he added.

"Many people think of CTLA-4 and PD-1/PD-L1 as interchangeable, but CTLA-4 is quite different in terms of how it regulates the immune system," said Sawyers. "In retrospect, earlier [treatment of] patients, and maybe the use of a CTLA-4 inhibitor instead of a PD-L1 inhibitor, or a combination, would be my recommendation [to examine in research going forward]."

In the trial, investigators set out to examine the safety and efficacy of atezolizumab in combination with enzalutamide versus enzalutamide alone in patients with mCRPC who had progressed on abiraterone acetate (Zytiga) and docetaxel or were not candidates for the taxane regimen. To be eligible for enrollment, patients had to have metastatic or locally advanced, incurable disease, an ECOG performance score of 0 or 1, and have received no prior immunotherapy or androgen receptor antagonist treatment.

Following a safety run-in, patients were randomized 1:1 to receive atezolizumab at 1200 mg every-3-weeks in combination with enzalutamide at 160 mg once daily or enzalutamide alone at 160 mg once daily. The primary end point of the trial was OS and secondary end points included prostate-specific antigen response rate, radiographic progression-free survival, objective response rate, and safety.

In total, 759 patients were randomized to either the doublet arm (n = 379) or the single-agent arm (n = 380). Results presented at the 2020 AACR Virtual Annual Meeting I showed no difference in OS between the 2 groups (stratified HR, 1.12; 95% CI, 0.91-1.37; P =.28). Specifically, the median OS was 15.2 months (95% CI, 14.0-17.0) in the combination arm versus 16.6 months (95% CI, 14.7-18.4) in the enzalutamide-alone arm.

Adverse events (AEs) were experienced by 96.5% and 91.8% of patients in the combination and single-agent arms, respectively, and proved to be consistent with those seen in the treatment components. Treatment-related AEs were observed in 77.8% of those who received atezolizumab plus enzalutamide and 51.1% of patients who were given enzalutamide alone.

Because the combination did not show an improvement in OS compared with enzalutamide alone, the study was terminated early.

In an interview with OncLive, Sawyers, a 2013 OncLive^® Giant of Cancer Care^® in Prostate Cancer; internist and hematologic oncologist; chair of the Human Oncology and Pathogenesis Program; and Marie-Josee and Henry R. Kravis Chair at Memorial Sloan Kettering Cancer Center, discussed the implications of the IMbassador250 trial, other notable presentations delivered at the meeting, and exciting research efforts being made in prostate cancer and beyond.

OncLive: The phase 3 IMbassador250 trial in mCRPC turned out to be negative. What can be learned from this research?

Sawyers: Obviously, I find [those results] disappointing. My own research is heavily invested in prostate cancer, albeit not on the immunotherapy side. I would point out that Padmanee Sharma, MD, PhD, of the University of Texas MD Anderson Cancer Center, discussed that abstract afterward and gave an excellent presentation. For those who want to learn more, I would encourage you to listen to her discussion. The key takeaway from her, which I agree with, is that the trial was done in patients with very late-stage [disease] and that may be too late to hope for an immune response to be reactivated.

Her own group at the University of Texas MD Anderson Cancer Center has shown that you can give immunotherapy to patients at diagnosis prior to surgery. A certain set of patients have locally advanced or aggressive disease in which it is meaningful to try new therapies to improve their chance of cure following surgery. She has shown that it is possible to elicit an immune response, if you treat early.

Another important point to make is that it really matters which immune checkpoint inhibitor you use. PD-1/PD-L1 can impact T-cells that are already present in the tumor and CTLA-4 can help recruit T-cells to the tumor. Earlier treatment and perhaps the use of a CTLA-4 instead of a PD-L1 inhibitor, or a combination, would be my recommendation.

Beyond this session, what were some other notable presentations that are catching your eye?

There was a session on the GENIE Project and how various investigators within the GENIE consortium or outside the consortium have used that data. GENIE is a consortium comprised of 18 cancer centers that have shared genomic and clinical data from patients who were being seen at their institutions. Full disclosure, I am the chair of the Steering Committee, so I was very proactive in getting this effort pulled together and I have seen the utility of the database grow with time. I was really thrilled to see how many different groups within and outside of the consortium have gone to that database to take their research questions to a higher level.

Probably the most compelling example that was presented yesterday came from my colleague Gregory J. Riely, MD, of Memorial Sloan Kettering Cancer Center, who showed the early results of curating the clinical outcomes of over 1000 patients with lung cancer; this was an extremely large data set and the curation was done using a novel approach called PRISM, which was developed at Dana-Farber Cancer Institute. What is powerful about it, is that those extractions were done over a 3-month period of time; in usual circumstances, it would have been a complete non-starter. However, using [what we’ve learned] from building this consortium and the shared expertise across different centers, we were able to develop this new way of generating the data more quickly. Most importantly, we are able to share [these data] openly. For all those reasons, that was my favorite session after the plenary.

What is your take-home message for your colleagues regarding this meeting?

First of all, it is such an unusual time and it was a bit of a risky decision to try and hold a virtual meeting like this. I do not know what the final number of viewers and registrants was, but I hear it was well north of many tens of thousands—so way more people than what could have been packed into the largest convention center. In some ways, maybe there is a silver lining [to what has been happening].

We learned that we can communicate cancer science widely and conveniently through this new forum. Of course, we all miss the rubbing of elbows after the sessions and having one-on-ones and networking meetings; however, on the other hand, the fact that so many people were able to see this science and ask questions in a virtual fashion [is impressive]. I see this as a positive development for how we can disseminate important science more broadly and quickly.

Are you working on any other research efforts?

I am happy to let people know about a really interesting work in prostate cancer that has been published in Science Magazine. For this work, we took a look at normal prostate tissue in mice and in humans using the lens of single-cell technology. We learned many interesting things about the composition of the prostate gland, its complexity, and how these cells behave. Please keep your eye out for this exciting research.

Sweeney CJ, Gillessen S, Rathkopf D, et al. IMbassador250: a phase III trial comparing atezolizumab with enzalutamide vs enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC). Presented at: the 2020 AACR Virtual Annual Meeting I; April 27-28, 2020. Abstract CT014. bit.ly/2WdOd5K.