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 spoke with Prostatepedia about the current state of affairs for immunotherapy for prostate cancer and what he anticipates happening in 2019.
“Over the past year, we’ve looked at early data from several anti- PD-1-based immunotherapy combinations. In 2019, we’ll be looking to see more results from these combination studies, to see which combinations will actually work in patients. It’s pretty clear that although PD-1 blockade has some activity, it doesn’t have a lot of activity. The idea is if you combine PD-1 blockade with some of the more standard therapies for prostate cancer, you might get more activity.
One of the more interesting combinations is PD-1 blockade plus a PARP inhibitor like Lynparza (olaparib). PARP inhibitors have activity in prostate cancer, particularly in patients who have mutations and proteins that repair DNA; these mutations are called called homologous repair defects. These patients have a good response to PARP inhibitors. A combination of PD-1 plus PARP inhibitors is being tested both in patients with the mutations and in patients without the mutations.
What has emerged in other diseases likes ovarian and breast cancer is that if one blocks PD-1 and treats with a PARP inhibitor, sometimes it looks like it doesn’t matter if the tumor has those DNA repair mutations or not. There are ongoing trials combining several of the anti-PD-1 / PD-L1 agents like Keytruda (pembrolizumab), Opdivo (nivolumab), and Imfinzi (durvalumab). All these drugs will be combined with PARP inhibitors. The question is whether that combination will lead to objective responses similar to what has been seen in other tumor types. Interesting early data from the NIH group suggest that the PARPi / anti- PD-L1 combination is active.
The second interesting combination involves PD-1 / PD-L1 blockade with hormonal therapy. We showed a while ago that hormonal therapy seems to at least temporarily block tolerance to prostate tumors in murine (mouse) studies. A vaccine plus hormonal therapy can lead to improved responses. The idea is that by giving initial hormonal therapy with immunotherapy, or adding an immunotherapy when you switch hormonal therapies, you will get better responses.
One randomized Phase III trial already tested this combination. The study enrolled patients who were on Zytiga (abiraterone) and then randomized them either to Xtandi (enzalutamide) or the combination of Xtandi (enzalutamide) plus a PD-L1 blocking antibody called Tecentriq (atezolizumab). I’m on the steering committee for that trial. Those patients were pretty healthy in general, though, and so it’s probably going to take a couple of years until we read out whether the combination leads to an improvement in survival.
Other PD-1 or PD-L1 blocking agents will be combined with hormonal therapy as well. At Columbia, we’re doing a really great trial called Magic-8. We’re giving anti-PD-1 in combination with the first hormonal therapy. This is for patients who have had surgery or radiation, who have evidence of a rising PSA, and have a fast doubling time. They will get the anti-PD-1 Opdivo (nivolumab) plus hormonal therapy with degarelix for a short course. Patients will first get two doses of immunotherapy— a prime and a boost. A month after that, they will get the combination of immunotherapy plus hormonal therapy with degarelix. They only get four months of hormonal therapy and then we stop everything to see if they can recover their testosterone and not have a PSA relapse.
To enroll in Magic-8, patients have to have had primary therapies, so they had to have either surgery or radiation. Then they have to have a PSA that’s rising quickly, with a PSA doubling time less than 12 months. Immunotherapy, as you know, is not without risk, so this trial is not for everyone. Patients have to have a reasonable indication that their recurrent prostate cancer is aggressive. They have to have a testosterone level greater than 200, so that their cancer will respond to androgen ablation. One thing that’s a bit different from other trials is that we don’t care if the patient has radiographically detectable metastases or not. If they have metastases, we’re asking them to agree to get a biopsy because we want to try to understand in which patients this combination works. Their PSA also has to be reasonable. It has to be more than 2 but less than 50. This trial is open and accruing.