Biomarkers, Combo Regimens Key to Mitigating AR-Resistance in mCRPC

Dana E. Rathkopf, MD

A number of clinical trials are seeking to identify beneficial therapeutic outcomes in patients with prostate cancer who are resistant to androgen receptor (AR)¬—targeted agents.

First, abiraterone acetate (Zytiga) is being tested in combination with the PARP inhibitor veliparib in a randomized phase II trial of patients with metastatic castration-resistant prostate cancer (mCRPC) who progress on androgen-deprivation therapy (ADT; NCT01576172).

Immunotherapy is also being explored here, too. Results of a phase II study, presented at the 2016 ESMO Congress, showed that the addition of the PD-L1 inhibitor pembrolizumab (Keytruda) to enzalutamide (Xtandi) in patients with mCRPC progressing on the AR-directed therapy may be associated with durable responses.¹

Out of the 20 enrolled patients, 4 achieved a confirmed prostate-specific antigen (PSA) reduction ≥50% and remained progression-free after 16 to 61 weeks. Additionally, 2 of the 4 PSA responders had measurable disease in the liver and lymph nodes and are evaluable for objective response; both achieved a partial response.

OncLive: Why is it important to understand AR-resistance in patients with prostate cancer?

What are some ongoing clinical trials specifically exploring this?

Where is apalutamide current at in development?

What ongoing work is there with PARP inhibitors in this space?

Why do you believe it has been so challenging to overcome AR resistance?

Is this along the lines of what the ARMOR3-SV study of galeterone was seeking?

What immediate steps can we take with biomarker development?

What advice can you give to community oncologists on discussing therapy resistance with patients?

In an interview during the 2016 OncLive State of the Science Summit on Genitourinary Cancers, Dana E. Rathkopf, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed strategies on the horizon to mitigate AR-resistance in patients with prostate cancer.Rathkopf: It is an exciting field because the AR is a very important target for prostate cancer. Actually, for prostate cancer, we have only had drugs approved with a survival benefit for targeting the AR for 5 years. So, our field is running to catch up and figure out who is the best patient to get AR-targeted agents and what the mechanisms of resistance are. Perhaps we can do combinations with chemotherapy, immunotherapy, or DNA mismatch-repair agents. It’s a very exciting time for the field.There are a couple of large phase III studies that have already completed accrual. There is an ALLIANCE study looking at the AR-targeted therapy enzalutamide versus enzalutamide plus abiraterone. There is also a phase III study looking at abiraterone alone or in combination with apalutamide, which is a second-generation AR-targeted agent, as well. It is an exciting time. We’re eagerly awaiting those results.Apalutamide is different from abiraterone and enzalutamide in that it has not yet been approved for use. It has shown efficacy in phase I and II studies, and there are several phase III registration studies looking at the drug ongoing, but it is not yet available for everyday patients who are not on clinical trials. The pressing question is, can this drug get approved in this space so we can make it available for patients in need?There is 1 study that was just completed by Dr Maha Hussain looking at a PARP inhibitor plus abiraterone. Then, there is another study that’s ongoing now that is going to look at abiraterone plus a PARP inhibitor and, excitedly, researchers are going to stratify it based on DNA-repair deficits. We are really looking forward to those results, as well.In prostate cancer, we need to find biomarkers to predict response and resistance. One exciting approach has been looking at AR-V7, particularly in circulating tumor cells (CTCs). Dr Emmanuel Antonarakis has done a lot of work on that in particular. The AR-V7 splice variant is an AR that doesn’t have a ligand binding domain (LBD). If you don’t have an LBD, then it makes it difficult to bind to testosterone, so the ARs are constitutively activated. The hope is, if we can identify those patients with AR-V7 variance, we may be able to use combinations or other drugs to overcome that resistance to AR-targeted therapy.In that study, they are going to stratify that based on AR-V7 status because galeterone may have activity in terms of AR-degradation. It may not be only dependent on the LBD to mitigate resistance with AR, so they will stratify that versus enzalutamide and look at the outcomes.The field is already doing that. Collaboration is key; no 1 institution can do it alone. There are groups of teams looking at different ways of looking at CTCs, and circulating tumor DNA. There is an enormous effort by Stand Up To Cancer, and they have already started to publish some of their findings. The future is right in our grasp.It is very difficult, particularly for patients progressing on an AR-targeted therapy because a lot of them have hopes, read the papers, and know friends who have been on these drugs for a long time. They tolerate these drugs very well but, at the time they start to progress, we don’t have the same options for them because sequential therapy with AR-targeted treatments has been underwhelming.

What are some of these other novel agents?

Is it beneficial to look at immunotherapy in this subset?

When we speak to patients, we need to be clear about not just the options we have available now, but the options we have coming in the future. That all comes back to overcoming resistance: combinations, identifying biomarkers, and new drugs that are on the horizon.You might imagine that targeting the N-terminal of the AR may have activity. There are drugs that may have activity against the AR-V7 splice variant through different mechanisms. In terms of the AR family, there is more to be done.It’s a great time to look at immunotherapy. It works in every other disease; it has got to work [in prostate cancer]. There was actually a recent study presented by Dr Julie Graff at the 2016 ESMO Congress. She looked at patients who were progressing on enzalutamide and then she continued enzalutamide and added a PD-L1 antibody.

Looking ahead, what do you hope is accomplished here within 5 years?

The responses were quite dramatic; there were 5 exceptional responders. They had very high PSA levels—1 patient had a PSA of 2000—and already received enzalutamide and progressed. She added the PD-L1 antibody and she saw that the PSA became undetectable. Not only that, but 2 patients had disease in the liver that regressed; they had a partial response. We are getting there, we are getting closer, and we should not give up on immunotherapy in advanced disease.If you think back to what has happened in the last 5 years, we didn’t have any AR-targeted therapies for mCRPC that were approved. The sky is the limit. I would like to see combinations come to fruition because there are very few diseases where monotherapy alone works. Combinations are an important field, biomarkers will be key in understanding and mitigating resistance, as well as choosing and selecting drugs based on genomic profiling. Not in 5 years, but I expect in 1 year, things are going to change dramatically.

Graff JN, Alumkal JJ, Drake CG, et al. First evidence of significant clinical activity of PD-1 inhibitors in metastatic, castration resistant prostate cancer (mCRPC). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 719O.