Looming Questions, Challenges Facing Physicians in Prostate Cancer

Wassim Abida, MD, PhD

Identifying biomarkers to determine who should receive chemotherapy, targeted agents, and immunotherapy is just one of several obstacles the prostate cancer community is currently facing, according to Wassim Abida, MD, PhD.

Abida, an assistant member and assistant attending physician in the Genitourinary Oncology Program at Memorial Sloan Kettering Cancer Center, led a panel discussion on major questions regarding the treatment of patients with prostate cancer during the 2016 OncLive State of the Science Summit on Genitourinary Cancers.

“It was a broad discussion of active questions in the field when it comes to treating patients with prostate cancer,” said Abida. “A couple of questions were related to using chemotherapy for patients with newly diagnosed metastatic disease and using targeted therapies for patients based on their tumor characteristics.”

OncLive: How do you choose between treating patients with chemotherapy versus targeted agents?

Abida sat down for an interview to explain the many unanswered questions researchers are determined to tackle, including identifying biomarkers, defects in DNA damage-repair genes, and understanding resistance to androgen receptor (AR)¬—targeted therapies.Abida: We have some answers. It’s truly clear that using early chemotherapy is effective and beneficial for patients with a lot of metastatic burden. The question is, “Is that good for patients with low-volume disease?” That was essentially a consensus among the panel. As far as that question goes, we have some answers but there are still unanswered questions.

What further research should we conduct?

What methods are we using now?

What are some additional exciting topics in the field of prostate cancer?

In terms of where the field is headed, there is a second question of whether we can select therapies based on tumor characteristics. That is an area of a lot of research where we don’t have any answers to yet, but there has been a lot of progress in that direction.We have really learned a lot about the biology of tumors recently; there is a lot of work from sequencing DNA from tumors in patients with prostate cancer. How do we take these findings to the clinic? How do we take these findings about the tumor characteristics, and pick treatments that will be individualized and beneficial to the patients? A lot of research is headed in this direction. It is confirming the findings from the biologic studies in the lab and, otherwise, taking that to the clinic and learning which patients may benefit from certain therapies.Right now, a lot of the effort has been directed toward DNA sequencing, but much of this requires a tumor biopsy. This has been difficult and impossible for certain patients. There has been a lot of effort and progress in doing DNA sequencing in blood samples from patients and looking at other tumor characteristics, including expression levels through RNA sequencing and characteristics of circulating tumor cells (CTCs) in the blood. Primarily, DNA sequencing has been the main focus of efforts to identify changes in the tumor that may be targeted through certain drugs.[In the panel discussion], a lot of time was spent talking about defects in DNA damage-repair genes that we are finding in a lot of patients. This could help with drug selection, so there is a lot of interest and enthusiasm about that type of therapy for patients with prostate cancer.

Have we made improvements in targeting AR and mitigating AR resistance?

Another question that came up is, “Where do we move up next with hormonal therapies in prostate cancer?” It surrounds targeting the AR axis where we have learned a lot about the biology of resistance and how we can exploit that going down the road.There are a couple different approaches for this. There may essentially be new ways of targeting AR that do not involve the classical drugs that target the C-terminal ligand-binding domains (LBDs). We need drugs that target other parts of AR. This is hinted at the increase of the AR-V7 splice variant that lacks LBD, which requires new targeted drugs. It may or may not yield responses, but it is an area that needs to be explored.

Is personalized medicine on the forefront of treating this disease?

The second is combination therapy. Both AR-targeted therapy, as well as other drugs, could possibly be added on that really induce responses when other pathways are [creating] resistance with 1 drug alone.Broadly speaking, it is really targeted therapy and personalized medicine. There is not going to be a single answer that’s true across the field for patients with metastatic prostate cancer in particular. It is going to be exploiting these defects in tumor cells individually for patients and using combination therapy to address these defects.

One area of huge excitement is using immunotherapy in prostate cancer. We have had more limited data in prostate cancer than in other diseases such as melanoma, kidney cancer, bladder cancer, but it is an area that we need to explore.

We need to identify those patients who may benefit from this novel type of therapy. It has really allowed for great responses in other diseases, and we would like to be able to exploit this in prostate cancer, as well.