7 Questions With a Prostate Cancer Expert on Immunotherapy

Immunotherapy may not be as prominent in prostate cancer as it is in other tumor types, but progress is still being made, says Akash Patnaik, an assistant professor of Medicine at the University of Chicago Medicine.

Aside from the immuno-based agent Provenge (sipuleucel-T), Patnaik discussed the status with immunotherapy and personalized therapy in an interview with CURE.

Patnaik discussed immunotherapy and personalized medicine tactics in the field of prostate cancer, as well as the work that needs to be done with existing targeted therapies and biomarker development.

What are the latest advancements with immunotherapy and personalized medicine in prostate cancer?

It is a very exciting time in oncology right now, with advances in precision medicine and a framework for understanding how some of these therapies that target specific aberrations in the tumor can ultimately lead to clinical benefit. There is also tremendous excitement and momentum with immunotherapies in a range of cancers—both solid tumors and hematologic malignancies.

However, there is still a subset of patients across all of these cancers who do not respond to immunotherapy. The challenge, particularly in the context of prostate cancer—which is one of the cancers where immune-based therapies have not been home runs—is that there have been limited successes, but clearly, there is room for improvement.

It will be challenging to understand how we can think about combinatorial approaches to enhance the efficacy and immunoresponsiveness of these cancers.

Are there immunotherapy combinations that are being studied right now in prostate cancer that have potential?

The only FDA-approved agent presently is Provenge, which is a vaccine-based therapy that has been shown to have a survival benefit in a phase 3 clinical trial. One challenge that remains with Provenge is determining the patients who are likely to benefit from this therapy. We do not have a biomarker yet that can identify the subset of patients who will respond.

The T-cell checkpoint blockade strategies have shown responses as well, but not strong enough to see a survival benefit with Yervoy (ipilimumab), for example. We are presently pursuing several mechanistically oriented combinatorial strategies, where we can explore oncogenic signaling pathways in the cancer and decipher overcoming resistance to these immune-based therapies using drugs that target oncogenic signaling.

Looking at the therapies that we do have available for patients with prostate cancer, do you find that there are challenges with sequencing?

In the context of metastatic castration-resistant prostate cancer, there have been several agents that have been FDA-approved since 2009. Therefore, the landscape has clearly evolved significantly in the last seven years. The jury is still out in terms of how best to sequence these therapies or even combine some of them. There are ongoing clinical trials that can answer some of those questions.

In terms of maybe comparing Zytiga (abiraterone acetate) and Xtandi (enzalutamide), how do you decide if you are going to administer one of those over the other?

What about Xofigo (radium-223 dichloride)? What is the optimal use of that agent?

What challenges are there in terms of finding biomarkers?

We essentially sequence them based on access to the agents, availability and reimbursement potential, which all need to be individualized for a given patient. It becomes a much more pragmatic decision in the clinic as opposed to a scientifically driven decision. In terms of the chronology of how these drugs were approved, Zytiga preceded Xtandi, and there is no clear consensus of which agent to give first. My practice pattern has been to typically give Zytiga followed by Xtandi. There is also a clinical trial looking at combining these agents upfront. There could be synergistic efficacy with those upfront combinations with Zytiga / Xtandi, given that their mechanisms of actions are non-overlapping.Xofigo has been discussed as a bone-targeted agent. Its predominant benefit lies in the subset of patients who have symptomatic bone metastases where Xofigo has been shown to have a palliative benefit and also a survival benefit. Typically, we reserve that therapy for patients with bone-metastatic disease that is symptomatic.There has been a sort of pie-in-the-sky view of biomarker development in the field. There are several challenges. In the context of precision medicine, the big challenge is tumor heterogeneity. Therefore, if a patient with a metastatic disease gets a biopsy, and we look for a specific biomarker that might predict for a response or lack of response to a given agent, there may be some cells that score positive and others that score negative for a given biomarker.

In addition, developing companion diagnostics from a drug-development perspective has its own set of challenges. There have been very few examples that come to mind where there has been a companion biomarker that has strongly predicted for response or lack of response. That is clearly where we want to go as a field, but there have been few examples— Zelboraf (vemurafenib) in BRAF-mutant melanoma and BCR-ABL—driven CML being responsive to Gleevec (imatinib).

Do you envision immunotherapy will play a larger role in the field in the next five to 10 years?

There are clearly examples where there has been an actionable biomarker, but a lot of solid tumors have multiple aberrations, and those aberrations cross over with each other; they are heterogeneous in the tumor microenvironment. These are all challenges that we are sort of grappling with in the field.Clearly, immunotherapy is here to stay. Across a range of cancers, there have been over a dozen malignancies at this point that have shown benefit. The challenge is going to be figuring out who is going to respond because, even in tumors such as bladder cancer, non—small cell lung cancer, renal cell carcinoma and melanoma, not all patients respond. We are very interested in understanding the immunologic bases for these responses.

There is likely not a one-size-fits-all approach. It is going to vary from tumor type to tumor type and also patient to patient. There are several mechanisms that can influence responses. All of those mechanisms need to be systematically evaluated to decipher the likelihood of response, and those will be important biomarkers for who will or will not respond to immunotherapy.