Combination Therapies in Advanced Prostate Cancer

Mario Eisenberger, MD

Today we are speaking with Dr. Mario Eisenberger, professor of urology and oncology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland. We are discussing potential new combination therapies for advanced prostate cancer that are currently being tested in clinical trials.

-Interviewed by Anna Azvolinsky, PhD

OncoTherapy Network: Dr. Eisenberger, let’s start with metastatic castrate-resistant disease. There are several trials that are now combining chemotherapy with the approved hormonal agents. Could you talk about some of these and the rationale for the combinations?

Dr. Eisenberger: Yes. The rationale is based on a principle of mechanisms of resistance to androgen receptor-targeted compounds, either abiraterone or enzalutamide. Frequently, what one sees is expression of a truncated mutant androgen receptor which is essentially a categorical mechanism for resistance to any androgen receptor targeted compound. This doesn’t appear to be the case with chemotherapy.

Our own data here at Johns Hopkins where the receptor was actually described and discovered, we found that the expression of a truncated androgen receptor does not preclude responses to chemotherapy. So I think we are beginning to see more clinical trials and the rationale is pretty strong, where instead of using a second, novel androgen receptor targeted compound, that is enzalutamide after abiraterone or vice versa, one is looking at chemotherapy with both docetaxel and cabazitaxel in that space.

There are also clinical trials currently combining chemotherapy together with a first novel androgen receptor targeted compound. That is, patients who develop evidence of disease progression with use of conventional, standard gonadal suppression with or without a first generation antiandrogen. These patients, when they progress, instead of being placed on abiraterone alone, they are now receiving abiraterone plus docetaxel or cabazitaxel, and these studies are also ongoing. I think this makes a bit more sense than combining androgen receptor targeted compounds to me, but there are other trials as well. Particularly, the Alliance trial that is combining standard abiraterone treatment with enzalutamide and this is in progress and we should learn more about how we should enhance the benefits from some of these newer compounds.

OncoTherapy Network: There is also an ongoing phase III trial combining abiraterone with radium-223 for men with chemotherapy-naïve metastatic disease. Is there preclinical rationale for this combination?

Dr. Eisenberger: There is a randomized phase II trial in which abiraterone plus radium-223 in combination. Yes, I think this is an option for patients. The rationale based on the biology is a little bit weaker. I think the reason to use this combination is you have two compounds that are approved and both provide a benefit as single agents, and we want to test whether these agents will work better when combined. There is also the combination of radium-223 with immunotherapy that is being explored and I think we will see more of these combinations with some of the approved drugs-chemotherapy and hormonal therapy and radiopharmaceuticals and immunotherapies. And I think that is very important because we need to understand what is the best approach, but we also need to understand what is the best sequence in which patients and what therapy to use.

OncoTherapy Network: Are there other combinations, including either targeted or immunotherapies, in later or early stages of development that you are looking forward to seeing the results of?

Dr. Eisenberger: Yes. There are several combinations of PARP inhibitors with standard, second-line hormonal therapies. There are PI3K inhibitors and AKT inhibitors, some of these inhibit more than one pathway and these pathways are overexpressed, abnormally, when patients progress on androgen receptor-targeted compounds. The question is whether adding one of these compounds to the androgen receptor-targeted compounds; both abiraterone or enzalutamide will improve the benefits. And I think this makes sense to test and the trials are ongoing and we will see how they read out.

OncoTherapy Network: Several of the approved agents for metastatic disease are also being tested for metastatic hormone-naïve prostate cancer. Are there recent results or ongoing trials you could highlight in this indication?

Dr. Eisenberger: All of these, enzalutamide, abiraterone, are being combined with standard gonadal ablation. Some of these are not approved, but they are being used. Some of the androgen receptor-targeted agents not yet approved, such as TAK-700, ARN509, are being tested in [hormone-naïve metastatic disease]. Of course, there are also chemotherapy trials. One is the CHAARTED trial and the other is the STAMPEDE trial that showed that adding 6 cycles of chemotherapy will reduce prostate cancer-specific mortality in patients who have metastatic, hormone-naïve, de novo prostate cancer. So I think the use of chemotherapy in that space is being re-emphasized and revisited. I think what we will see is a change in the paradigm for those patients who present with castration-resistant disease and who have received chemotherapy in the hormonal sensitive setting. How we treat the castration-resistant prostate cancer will evolve because of these trials. Androgen receptor-targeted therapies, immunotherapies, and also radiopharmaceuticals are all now being tested in the hormone-naïve setting.

OncoTherapy Network: Thank you so much for joining us today, Dr. Eisenberger.

Dr. Eisenberger: OK, my pleasure.