Expert Shares Insight on Immunotherapy, Emerging Strategies in Prostate Cancer

David R. Wise, MD, PhDD

2018 may be the year that checkpoint inhibition breaks through in the treatment landscape of prostate cancer, according to David R. Wise, MD, PhD.

Currently, the only immunotherapy approved specifically for the treatment of patients with prostate cancer is sipuleucel-T (Provenge); however, checkpoint inhibitors, such as pembrolizumab (Keytruda), are showing promise in the castration-resistant setting.

Beyond immunotherapy, PARP inhibitors are also showing promise as investigators continue to understand the genetic implications of the BRCA1/2 gene beyond its significance in breast and ovarian cancer. Not only are these 2 types of therapy showing early efficacy as single agents, but they are beginning to be investigated in combination, as well.

OncLive: Can you please provide an overview of your presentation?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Genitourinary Cancers, Wise, an assistant professor at NYU Langone’s Perlmutter Cancer Center, discussed the promise for immunotherapy and other emerging approaches in the field of prostate cancer.Wise: I gave an overview of some of the newer approaches for prostate cancer treatment. I covered some of the recent advancements in novel androgen receptor (AR)-directed therapies for use in advanced prostate cancer, with the theme of "earlier is better.” Using our more effective and very well-tolerated therapeutics in patients who present with newly diagnosed metastatic non—castration-resistant prostate cancer has dramatically improved outcomes, and our patients are already benefitting from them. We took more of a granular look at those studies and analyzed some of the limitations, but also some of the nice results and how to apply them in the current clinical setting.

I also spoke about some newer advances in terms of precision oncology, how we are looking at the specific genetic features of our patients' cancers and using those to guide our clinical trial design and decision making. Hopefully, this will soon include actual clinical decision-making with the use of FDA-approved agents.

In terms of AR-directed therapy, what are some of these recent advances?

Apalutamide has been granted priority review status for nonmetastatic CRPC. If that agent is approved, what potential impact could it have?

Are there any current clinical trials that are showcasing examples of precision medicine?

I ended with some of the things that are on the horizon in terms of bringing immunotherapy into prostate cancer. Many have been waiting for those advances that have been so exciting in other cancer types to make their way into prostate cancer practice. What created a lot of buzz at the [2017 ASCO Annual Meeting] was the use of abiraterone acetate (Zytiga) with prednisone. We know it’s an approved agent for patients with metastatic castration-resistant prostate cancer (mCRPC), whether pre- or post-chemotherapy; however, what wasn't clear was whether the use of it in patients who were newly diagnosed or recurrent with non—castration-resistant prostate cancer with high-risk features would be beneficial. That is what we are looking into a bit closer tonight—these 2 presentations made at the 2017 ASCO Annual Meeting of the LATITUDE and STAMPEDE trials, and the outcomes and potential limitations of these studies. It will shift the landscape. We do see patients with nonmetastatic CRPC; some would term it rising prostate-specific antigen (PSA) that is castration-resistant. I would speculate that apalutamide will become an important treatment option for those patients who are high-risk, as those with castration-resistant disease are, even if their disease is not metastatic. We will see that included in our armamentarium that we have available to us, and other trials are going to be reported soon in that nonmetastatic context with enzalutamide (Xtandi) and darolutamide (ODM-201). That is a pretty crowded space with some therapeutics that are generally well tolerated, so there is a lot of interest and enthusiasm about that. We are excited about this on several fronts. At NYU Langone’s Perlmutter Cancer Center, we have several trials that are investigating precision oncology hypotheses directed at the main genetic features of cancer that we are seeing in our patients. One involves the cancers that have DNA-repair defects, and those are cancers that have BRCA1/2 and are better known for causing hereditary breast and ovarian cancer. However, what is less appreciated is that men are affected by these mutations, as well. First-degree male relatives of female carriers of the BRCA1/2 gene are at risk and should undergo genetic testing. The flip side of that is we have found that those genetic features to be quite sensitive to a newer class of compounds called PARP inhibitors in earlier-phase studies.

NYU Langone’s Perlmutter Cancer Center has 2 trials available right now with 2 different strategies incorporating the same PARP inhibitor, rucaparib (Rubraca). We have another trial that is combining a newer PARP inhibitor called talazoparib with a PD-L1 checkpoint inhibitor, and we are hoping to see some synergism between the 2 agents.

We have been waiting to hear positive data with checkpoint inhibitors in prostate cancer. Do you foresee any progress this year?

Finally, there is another strategy for which the hypothesis has been around for many years. We are starting to see more specific and potent agents that could take advantage of defects in the PTEN-PI3K pathway, which we are seeing in a very high percentage of patients with prostate cancer. That is the high-level view of what we have available. We as a community hit a significant road block in the initial generation of study looking at nivolumab (Opdivo), in which there was not a single response in the initial 17 patients with castration-resistant prostate cancer. That really left people thinking that prostate cancer was not going to be sensitive to checkpoint blockade. However, in fact, that is beginning to change. At NYU, we are heavily investing in newer immunotherapy approaches.

Progress has begun to be seen with the pembrolizumab studies that were reported and published on the first 10 patients with stage III castration-resistant disease. Those patients had substantial responses to pembrolizumab. There was also an abstract from the 2017 ASCO Annual Meeting showing that, in the fuller 20-patient cohort, there were 5 responses; that 20% response rate is not that different from other cancer types.

Is it too early to know which patients may benefit from checkpoint blockade?

Aside from PARP plus immunotherapy, what other strategies are being explored?

We are very interested in this idea, and we are especially interested in the convergence of these 2 areas—BRCA family member—associated cancers and PD-L1, in which we have a trial now testing it in combination with avelumab (Bavencio) and talazoparib. PARP inhibitor treatment might actually induce an inflammatory microenvironment that may promote immune-based surveillance and tumor killing that could potentially be furthered or augmented with the effects of PD-L1 blockade. We are very excited about that study. It is a bit early. That is being investigated, but I will say that prostate cancer, in a way, is often not given the same level of attention for some of these newer advances. We are trying to be advocates for our patients and move that research along, despite the fact that it is not in the mainstream right now. Therefore, we are looking at a number of biomarkers that might predict a better response to immunotherapy, and we are also trying to develop new patient-derived models in the lab that could look for signals of sensitivity to immunotherapy. Definitely. We are actively investigating the next waves of basic science heading into cancer treatment. One of the ones generating a lot of excitement is epigenetics, which is the ability of signals from outside of the cell to modulate the cellular DNA in a way that is not inheritable but is quite robust in terms of its ability to affect cell signaling.

What else would you like to highlight?

We have an active trial right now testing a set of hypotheses revolving around the Bromodomain and Extra-Terminal Domain (BET) proteins—the bromodomain proteins of BRD1 through BRD4. We have an active inhibitor of that target, which we are testing in combination with either abiraterone or enzalutamide in patients who have progressed on that agent, in hopes of resensitizing the tumor to the effect of those drugs.At NYU, we are really furthering prostate cancer research from multiple angles. The one that we haven't talked about enough but is going to become increasingly important is prostate cancers that begin to lose their PSA expression. As prostate cancer progresses, we typically see continued production of PSA and continued dependence on the AR, which explains the effectiveness of abiraterone and enzalutamide and now apalutamide. The subset of patients who we see the progression of prostate cancer in the absence of PSA and AR-dependency is an area of significant unmet need, because our AR-directed agents are completely ineffective in this population.

We are going to be opening a study at NYU looking at that specific population and testing a new immunotherapy strategy in that population, as well. There is convergence of basic science and important translational clinical work that is happening at NYU that we are excited about and hope will be able to help our patients.