Expert Sees Checkpoint and PARP Inhibitors Building on mCRPC Success

Paul G. Corn, MD, PhD

There may not yet be a cure for metastatic castration-resistant prostate cancer (mCRPC), but with a plethora of agents available and potentially more on the horizon, experts in the field should feel hopeful about the future, according to Paul G. Corn, MD, PhD.

“My perspective is that, for a long time the treatment of patients with mCRPC was probably considered to be somewhat nihilistic,” said Corn, associate professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.

“Now, we have 6 new drugs, we have research that suggests there are more on the horizon, and patients are clearly living longer. I certainly feel quite hopeful when I meet my patients that, granted, we don’t have a cure yet, but we are definitely improving patients’ outcomes with a good quality of life.”

Corn lectured on treatment options for mCRPC during the 2017 OncLive^® State of the Science Summit on Genitourinary Cancers. In an interview during the event, Corn spoke on the recent advancements in mCRPC treatment, exciting ongoing research with PARP inhibitors and other agents, and why he still holds hope for immunotherapy in this field.

OncLive: Can you provide a summary of your discussion on mCRPC?

Corn: I talked about treatment of mCRPC and the main theme is that there are actually an increasing number of agents that are now available and FDA approved to treat mCRPC. It is actually a very exciting time to be a prostate cancer clinician and researcher because of the number of successful agents.

At the same time, the number of new agents has created some challenges, particularly around sequencing and combinations. I presented some of the principles of treatment that organizes how we have approached treating this disease, as well as highlighted some of the research efforts we hope academicians and community oncologists understand how to best sequence these novel agents.

The most exciting avenue of research is the possibility that we can develop predictive biomarkers to individualize therapies for individual patients. At The University of Texas MD Anderson Cancer Center, we employ frequent tumor biopsies similar to what they do in leukemia to understand the temporal heterogeneity of this disease over time.

There is some exciting research going on at different institutions so that we can eventually perform a biopsy, for example, and then actually understand what the best drugs are to apply for individual patients.

What novel agents have really propelled the field forward?

There are 3 categories of agents I divide based on their mechanisms of action. The major category would be drugs that block androgen receptor (AR)-signaling, so 2 of the more exciting agents that have been approved in the last several years include abiraterone acetate (Zytiga) and enzalutamide (Xtandi).

Those are excellent drugs with very tolerable side effects that both have been shown to prolong life, and they really work on the principle that tumors that adapt to leuprolide (Lupron) still rely on testosterone for growth. There is a category of drugs that we believe will continue to work even after abiraterone and enzalutamide, but those are in development.

The next category of drugs remains to be chemotherapy. Chemotherapy is a very important class of drugs that works through a different cytotoxic mechanism. In addition to docetaxel, there is cabazitaxel. Research efforts are ongoing to identify chemotherapy combinations; one in particular are platinum-based agents, which are being restudied and resurrected as having a role in the treatment of patients with prostate cancer.

The third category is the immune therapies. Sipuleucel-T (Provenge) is a bonafide prostate cancer vaccine that exists to treat patients with CRPC. There are efforts to understand how checkpoint inhibitors might work in prostate cancer and that’s an area of active research.

There is a really a fourth category of novel therapies, as well, which is the recent identification that patients who harbor mutations in DNA-repair proteins are sensitive to PARP inhibitors.

There are agents that exist in each of these categories and exciting research that we hope will propel each of them.

With these treatments available, how do you decide which to administer first?

In general, for patients who progress after standard hormone therapy—even those who got docetaxel as part of the CHAARTED paradigm—we typically would offer them additional AR-blocking agents, such as abiraterone or enzalutamide. There are some exceptions to that.

We have identified a subset of patients who seem to be indifferent to AR-targeted agents or would be predicted to have very low-quality responses to abiraterone or enzalutamide, and those patients are more likely to be shuttled toward chemotherapy.

For patients who are on abiraterone or enzalutamide and start to progress, but remain relatively symptom free, that’s a space we’re a little morel likely to employ sipuleucel-T or radium-223 dichloride (Xofigo). I’m very much influenced, again, by the presence of symptoms or not and the degree of progression in deciding to offer chemotherapy. However, chemotherapy is a very valid option. In other words, it shouldn’t be avoided because our chemotherapies are generally well tolerated.

Will chemotherapy continue to have a place in the prostate cancer treatment paradigm?

That’s a great question. For the foreseeable future, I think that it will be. There might be improvements on curing patients with high-risk localized disease that might reduce the number of patients who develop CRPC but, for the foreseeable decade, it’s likely that chemotherapy will continue to have a role, in my opinion.

Are there any potentially practice-changing studies ongoing with either abiraterone or enzalutamide?

Yes. There clearly are some phase III studies that I reviewed to answer the question of sequencing. One of the points I made was the impossibility of considering all of the options. There are a number of phase II studies now that certainly understand the feasibility of combining some of these agents; for example, abiraterone with sipuleucel-T, or abiraterone plus chemotherapy are 2 such trials. It is clear that we will get some patient experience to help guide us, but it seems to me that it will likely remain a challenge.

This is because the number of drugs we have and the pace of research are essentially outpacing our ability to understand all of the permutations by phase III trials. The prospective of our research endeavor at The University of Texas MD Anderson Cancer Center is that we can come up with a biomarker-driven approach. For example, we think that patients with no likelihood of responding to AR-blockers can be considered for other options, such as chemotherapy or PARP inhibition—things like that.

We have seen the effect of immunotherapy in various solid tumors, but it seems like it’s still being figured out in prostate cancer. What do we know so far based on data that have been released?

We still believe that the checkpoint inhibitors hold great promise in treating CRPC. The phase III studies were perhaps statistically negative, but it’s clear that a subset of patients actually benefits—at least with ipilimumab (Yervoy). A combination of these drugs may be required. I still believe that this is going to be an incredibly important avenue of research, and it’s something that, again, our institution is passionate about.