Dr. Fatima Karzai is the Director of the Prostate Cancer Clinic for the Genitourinary Branch at the National Cancer Institute. She’s keenly interested in developing novel strategies for harnessing the power of the immune system for hormonally driven cancers, particularly in advanced prostate cancer.
Prostatepedia spoke with her about a clinical trial she’s running that combines PARP inhibitors and a class of immunotherapeutic agents called PD-L1 inhibitors in men with advanced prostate cancer.
Why did you become a doctor? What is it about medicine that keeps you interested?
Dr. Fatima Karzai: I decided to become a doctor at a very young age. I’ve always wanted to help people. When I was younger, I thought that being a doctor was the best way to do that. I really enjoy patient interactions, so that’s why I’m a clinical researcher and I see patients on clinical trials. I find that it’s the most rewarding experience to be able to interact with patients. It’s always been a goal of mine to be able to help people in this manner. I think oncology was best suited for me to do so.
What are PARP inhibitors and PD-L1 inhibitors? How do they work, in which patients are they used, and how effective are they?
Dr. Karzai: PD-L1 inhibitors are members of a group of drugs called checkpoint inhibitors that have been developed for the treatment of cancer. PD-L1 is a protein that is present on the surface of cells. In cancer, PD-L1 on the tumor cells interacts with another protein on a person’s white blood cells, which are immune cells that help fight cancer. This PD-L1 protein prevents the immune system from attacking the tumor cells. A PD-L1 inhibitor blocks that ability of the tumor cell to suppress our immune system, which can help our immune system kill cancer cells. They’ve been successful in certain cancer types like lung cancer and bladder cancer.
PARP inhibitors are a type of targeted therapy. We all have DNA in our bodies; when it becomes damaged, our bodies know how to repair it. Many things can cause DNA damage: exposure to UV light, radiation, or substances in the environment. There is an enzyme in cells called PARP. PARP helps repair DNA when it becomes damaged. By blocking PARP in cancer cells, we can keep cancer cells from repairing their damaged DNA, which causes them to die. PARP inhibitors work very well in a subset of patients whose tumors harbor something called “DNA damage repair mutations.” These mutations can occur in the tumor itself or it could be something that a patient is born with. PARP inhibitors were initially studied in ovarian cancer and breast cancer. We’re starting to use them more in prostate cancer.
What is the rationale between combining the two agents for prostate cancer?
Dr. Karzai: We wanted to expand the use of PARP inhibitors. Like I mentioned before, right now they’re used in patients with these specific mutations. We’re trying to figure out if we’re able to get this class of drugs to work in patients without these mutations if we combine them with another drug. Historically, PD-L1 inhibitors have not been that successful in prostate cancer, so we decided to put these two drugs together to see if there is any additive or synergistic mechanism that could help patients with advanced prostate cancer.
What have the studies revealed about the combination?
Dr. Karzai: We are still accruing to the study. We’ve looked in-depth at the first 17 patients and seen deep and prolonged responses in men with castrate-resistant prostate cancer with the combination, in men who have these germline or somatic DNA damage repair abnormalities. We’re now adding additional patients to the study to better define the activity and to help us evaluate the biology more.
You said you’re still looking for more patients?
Dr. Karzai: Correct.
Tell us a little bit more about eligibility criteria and who men can contact if they think they’re a fit.
Dr. Karzai: We are looking for patients with advanced prostate cancer—i.e. the prostate cancer has gone outside the prostate and is in either the soft tissue, organs, and/ or bones. We would like to have these patients previously treated with either Zytiga (abiraterone) or Xtandi (enzalutamide). We think patients who have progressed on these two treatments might be more amenable to our combination. We allow previous chemotherapy, so if a patient has had Taxotere (docetaxel) or some other chemotherapy, they would be eligible. We are looking for patients who are still able to perform their activities of daily living and would be willing to participate in our trial and travel.
Some of our patients are local, but many come from across the United States. We even have some international patients.
You help defray the cost of travel for some of your clinical trial participants, don’t you?
Dr. Karzai: We do. Once a patient is on one of our protocols, then we reimburse flights in the United States. We also have a stipend for meals and hotels.
Any further thoughts on this particular combination or other combinations that you think may hold promise?
Dr. Karzai: Even though this type of immune therapy hasn’t been very successful thus far in prostate cancer, I still think that we need to do more studies and research to be able to find the subset of patients that it might work in. Immunotherapy is very exciting. We shouldn’t count it out in prostate cancer yet. The first vaccine that was FDA-approved in cancer was actually for prostate cancer. I think that the whole realm of immunotherapy is still open and could provide benefits for our patients. I am happy to see any patient for a consultation —those with newly diagnosed disease or those who are more advanced. We have clinical trials that span that spectrum of prostate cancer.