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Studies of immunotherapy for prostate cancer yield encouraging results
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Several studies designed to investigate immunotherapies and immunotherapeutic combinations for treatment of prostate cancer have yielded encouraging results.
Sumit K. Subudhi, MD, PhD, assistant professor of genitourinary medical oncology at The University of Texas MD Anderson Cancer Center, and colleagues in MD Anderson’s Prostate Cancer Moon Shot program are investigating immune-inhibitory pathways in the prostate cancer microenvironment.
They found that the tumor upregulates PD-L1 and VISTA inhibitory molecules in response to monotherapy with ipilimumab (Yervoy, Bristol Myers Squibb), an anti-CTLA-4 antibody.
Therefore, they are investigating the combination of ipilimumab plus the anti-PD-1 therapy nivolumab (Opdivo, Bristol-Myers Squibb), as well as the anti-PD-L1 agent durvalumab (Imfinzi, MedImmune/AstraZeneca) plus the anti-CTLA-4 therapy tremelimumab (AstraZeneca) for men with metastatic castration-resistant prostate cancer.
They also are trying to target immunosuppressive cells within the tumor microenvironment with the CD38 antagonist daratumumab (Darzalex, Janssen) in a high-risk cohort of men with localized disease.
HemOnc Today spoke with Subudhi about the challenges of immunotherapy in prostate cancer, the hurdles investigators still have to clear, and the directions in which future research likely will go.
Question: Why has immunotherapy been a challenge in prostate cancer?
A: There are a number of reasons. Prostate cancer is more of what we call a cold tumor, compared with a hot tumor like melanoma. This means there are more immunosuppressive cells that shut down T cells, which are the main players in immune checkpoint therapies. Another reason is that 80% of the time, prostate cancer metastasizes in the bone, which also appears to be a highly immunosuppressive environment. There is an underappreciation of the bone microenvironment. The third issue is that patients are medically castrated. Testosterone is food for that cancer, so hormonal treatments involve lowering testosterone levels and/or blocking the protein it binds to on the cancer, the androgen receptor, to starve the cancer. These approaches somehow impact the immune system. We believe in some settings it can help and in other settings it can hurt.
Q: Is immune therapy for this population just speculation at the moment?
A: Thus far, results from preclinical studies are showing that what we are doing can actually help. In some data sets, we’ve seen that lowering testosterone levels can help the immune system, but other therapies that target the androgen receptor can inhibit the immune system. Basically, we haven’t done a good job of dissecting these complicated factors and questions.
Our team is currently dissecting each of these factors. We know T cells are important. We need to boost their activity so they can kill the cancer. In other studies, we’re targeting immunosuppressive macrophages and T cells, seeing if they can help with immune checkpoint therapy to make tumors hotter as opposed to colder. Hopefully we will start to have some answers soon. We also have trials combining hormonal therapies with immunotherapies in the hopes of improving survival.
When we give immune checkpoint inhibitors, we see upregulation of PD-L1 and VISTA, which makes the tumors even more immunosuppressant. It is for this reason that, in prostate cancer, you have to use combination therapies as opposed to a single approach. T
Q: Do you see increased adverse events or drug-drug interactions with these combinations?
A : We have seen some more adverse events, but not so many drug-drug interactions. When you give drugs that impact the immune system, you see more immune-related side effects. In particular, we’re seeing a lot of colitis, which is inflammation of the colon that often manifests as diarrhea. These are all consistent with what our colleagues in melanoma or kidney malignancies have seen.
Q: Does the future look bright for these combinations?
A: In the next few years, we’ll find the right combination to make immunotherapies more effective in prostate cancer. Right now, though, I still think we have more work to do. That includes borrowing strategies from our colleagues in other cancers. For example, our colleagues in lung cancer have segregated cancers histologically. They have further segregated them molecularly. All of this information helps clinicians decide what therapy any given patient should get. In prostate cancer, all we have is Gleason score. We treat all patients as though they have the same prostate cancer. Data are now showing that there are different subtypes in terms of hormonal involvement. They are androgen receptor sensitive or indifferent. We think that the indifferent tumors are probably more immunosuppressive than the receptor-sensitive tumors.
Q: What types of outcomes are you assessing?
A: One of the outcomes in prostate cancer is RECIST criteria. But if 80% of patients with metastatic disease have it in the bone and 50% or more have no measurable disease, you can’t even use RECIST. It’s a challenge to tell if someone is doing well apart from PSA, but PSA doesn’t always correlate with success. One of the things we’re finding as we publish papers and have more long-term follow-up is that time to next systemic therapy and yearly survival rates are panning out as a useful outcome. Even though their scans may be inconclusive, if the patient is telling me they feel good, maybe they’re not ready to make a change in their therapy. This type of clinical decision-making could be a useful.
Q: So, in a way, looking back at how therapies have performed in the past may actually shed light on what may work in the future.
A: That’s a great point. What we’re finding is that some of the therapies we use might change PD-L1 expression within the tumor. We actually have a trial opening up in the next couple of months looking at patients who have progressed with second-generation hormonal therapies, which are thought to increase PD-L1 expression within the prostate tumor, and we will be treating these patients with an androgen receptor antagonist apalutamide (Erleada, Janssen) plus anti-PD-1. Patients are letting us biopsy them two or three times during a trial, which allows us to determine if we’re making the right change in the tumor. They are giving us such a valuable gift by doing this. This is helping us to learn whether the change in therapies is helping them. – by Rob Volansky
Reference:
Gao J, et al. Nat Med. 2018;doi:10.1038/nm.4308.
For more information:
Sumit K. Subudhi, MD, PhD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1374, Houston TX 77030; email: sksubudhi@mdanderson.org.
Disclosure: Subudhi reports a joint scientific committee role with Janssen.