Expert Projects Next Steps in Advanced Prostate Cancer

Russell Szmulewitz, MD

As researchers now look to determine the optimal use and sequencing of these agents, other targeted therapies and immunotherapies are advancing through clinical trials, says Russell Szmulewitz, MD.

OncLive: What are the biggest questions right now in the field of mCRPC?

In an interview during the 2016 OncLive State of the Science Summit on GU and Prostate Cancer, Szmulewitz, associate director of the Genitourinary Oncology Program, assistant professor of Medicine, the University of Chicago Medicine, discussed optimal treatment strategies for patients with mCRPC and highlighted emerging therapies in the therapeutic landscape.Szmulewitz: Prostate cancer is a cancer that we think of and treat in clinical stages and, from localized through non-castration or castration-sensitive metastatic to castration-resistant, the risk of disability and death increases the further on the spectrum you are.

What are the most exciting advancements that you have seen occur?

We have seen, over the last 5 or 6 years, several new therapies get approved for metastatic prostate cancer that is castration-resistant, and it is really changing the landscape quite dramatically. However, there is a lot that we do not know, such as how to sequence these medicines, or what pathways of resistance are common—should we try them all? We do not know what therapeutic targets we should focus on when we are dealing with patients who have already received all of these new standards of care.It has been quite exciting to have validation that the androgen receptor is a bona fide viable target. The harder we hit, the bigger the impact that we can have. The earlier we move it in castration-resistant disease, the bigger the magnitude we can have in both delaying death, deterioration of quality of life, and time to initiation of pain medicines for cancer-associated pain and things of that nature. It is not only extending life, but it is really improving quality of life.

With a variety of therapies to choose from, how do their associated adverse events play a factor in how you choose the treatment?

The other thing that we are now understanding, and has been exciting, is that the biology of castration-resistant prostate cancer really evolves under the therapeutic pressures that we give. We now understand that there are androgen receptor splice variants that do not require androgen to be active and likely confer resistance to some of these medicines. How we target those is not quite clear, but at least we now know that we are going to have tools to sort of select who is appropriate for what. We also know that a fair number of patients have mutations that evolve in their prostate cancer and might benefit from very specific targeted therapies.When we are deciding between 2 or 3 drugs that are approved for the same indication in the same space, there are several factors to consider. For example, I have abiraterone acetate, which perhaps has high blood pressure, low potassium, and fluid retention as potential adverse effects. It comes with prednisone, which has its own set of adverse effects, including increased blood sugar and things of that nature. Therefore, for patients who have poorly controlled blood pressure or poorly controlled diabetes, we might choose something such as enzalutamide, which is similarly beneficial.

What ongoing clinical trials are you excited about in mCRPC?

However, if patients are potentially frail or have more joint pain, perhaps I would not go with that medicine, but with abiraterone acetate first. There are also cost considerations that come into this, but having more than 1 therapy approved in the same place helps us with respect to adverse effects.There are immunotherapy clinical trials adding sipuleucel-T to other agents. There is a phase III trial with ipilimumab (Yervoy) that has not yet read out. That is in the prechemotherapy castration-resistant setting, and we look forward to those results.

How would you describe how far we have come in this field, and where we are headed?

There are new androgen receptor—modulating agents that we think may have activity even against the splice variants that are just getting started—galeterone being one of them—and so those are therapies that we will be changing the landscape in. Finally, I think DNA repair pathway agents, olaparib (Lynparza) [will play a role]. There are some very eye-opening data of olaparib in patients with certain DNA repair defense to their cancer, so that is something that we are excited to see.In the next 5 to 10 years, we are going to see 2 things. One, we are going to see some of the drugs that we already have move forward into the hormone-sensitive or castration-sensitive disease—a move in the preoperative space.

We are also going to see more molecular diagnostic—driven therapeutics. We will be getting more biopsies, characterizing mutations, and we will be treating those mutational deficiencies—the DNA repair being 1 example. In the next 5 years, we are going to see more of that. For patients with amplifications of certain genes, we will treat with inhibitors [of those genes].

Over the past several years, the FDA approval of several novel agents has revolutionized the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).