Dr. Charles G. Drake is the Director of Genitourinary Oncology, Co-Director of the Cancer Immunotherapy Program, and Associate Director for Clinical Research at the Herbert Irving Comprehensive Cancer Center, New York-Presbyterian/Columbia University Medical Center He frames this month’s Prostatepedia conversations on immunotherapy.
This is a fascinating time for immunotherapy in prostate cancer.
For the first time, we have a randomized, Phase 3, 800-person trial combining immunotherapy with hormonal therapy. This trial looks at Tecentriq (atezolizumab), a Genentech agent. Patients with metastatic castrate-resistant disease who have progressed on Zytiga (abiraterone) are randomized to Xtandi (enzalutamide) alone versus Xtandi (enzalutamide) plus Tecentriq (atezolizumab). Although there are not a lot of Phase II data supporting this regimen, this is a bold trial concept that could lead to immune checkpoint blockade being FDA-approved for some patients with metastatic castrate-resistant prostate cancer (mCRPC).
On the other hand, in some quarters there is still a lack of enthusiasm for PD-1/PD-L1 blockade in prostate cancer. This lack of enthusiasm is based on older data from the original Opdivo (nivolumab) Phase 1b trial, which included 17 patients with mCRPC. We also didn’t see many objective responses in the anti-CTLA-4 (ipilimumab) Phase 3 trials. This lack of response led to the idea that combination therapies will be needed to go forward. This is not unique to prostate cancer.
Combinations range from immunotherapy-immunotherapy combinations, which are mostly in Phase 1 and 2 trials, to immunotherapy-hormonal therapy combinations, one of which is in Phase 3. In addition, Dr. Doug McNeill has done some nice work combining anti-PD-1 with DNA vaccines. Dr. James Gulley and his colleagues at the National Institute of Health tested similar combinations using anti-CTLA-4 plus ProstVac VF. Other combinations include combined immune checkpoint blockade. Dr. Emmanuel Antonarkis at Johns Hopkins University is leading a trial combining CTLA-4 plus an anti-PD-1 in high-risk (ARV7 splice variant) patients. A second, larger trial of that same combination is being conducted at MD Anderson Cancer Center.
In her conversation, Dr. Naomi Haas talks about the idea of using adoptive T cell therapy, either in the form of chimeric antigen receptor T cells (CAR T-cells) or in the form of adoptive T cell therapy. I think that is a fascinating therapy that hasn’t been brought forward in force in prostate cancer. Dr. Haas and her group launched a trial of PSMAtargeted CAR T-cell. There is a lot of enthusiasm in the field about that trial. It’s worth noting that Dr. Susan Slovin at Memorial Sloan Kettering Cancer Center has also been doing groundbreaking work in adoptive T cell therapy. I think it’s an exciting time for those therapies.
The success of drugs focused on patients with DNA mismatch repair mutations—PARP inhibitors— has led to the idea of combining immunotherapy agents with them. The folks at National Cancer Institute (NCI), particularly Dr. Ravi Madan, have generated fascinating data on those combinations. This work is moving forward at the NCI and in larger trials combining PD-1 blocking drugs with agents like Lynparza (olaparib) and Zejula (niraparib). The early data generated by the NCI group are quite exciting. We’ll see how this shakes out either with other agents or in larger datasets. Overall, it is very interesting.
I’ve been working on immunotherapy for prostate cancer since 2000. We went from irrational optimism about vaccines alone to a bit of depression when some of the large vaccine trials weren’t particularly successful, and as they continue to be unsuccessful as monotherapies. Also, Dr. Tomasz Beer, Susan Slovin, and myself all had cautious optimism about CTLA-4, which very nearly achieved its primary endpoint in a randomized Phase 3 registration trial. That has given way to guarded optimism that we’ll eventually figure this out.
Finally, I’ll add that there are plenty of clinical trial opportunities for prostate cancer patients. But many times, patients jump into the next therapy after one therapy fails, and they do not take some time to carefully consider their clinical trial options. In my experience, prostate cancer patients sometimes seem a bit stunned when they learn that they’re progressing. This is totally understandable. But for many patients, a very reasonable option is to think carefully about which trials might be available to them. One information source is http://www.clinicaltrials.gov, but simply bringing up clinical trials with their treating oncologist is a great first step.