Dr. Fleming is a genitourinary medical oncologist at Virginia Oncology Associates, where he coordinates the Genitourinary Research Program and leads the Phase 1 Program. Additionally, he is the medical director of Sarah Cannon Research Institute’s Genitourinary Committee. Dr. Fleming is considered a leading world expert in novel therapy research in genitourinary oncology and is credited with helping develop and investigate the oral androgen-receptor-signaling inhibitor enzalutamide in metastatic castration-resistant prostate cancer.
In an exclusive interview with GU Oncology Now, Dr. Fleming details his career journey—highlighting the mentors who were critical to his success—along with his clinical trial work that has had and continues to have the largest impact on patients with genitourinary malignancies, especially those being treated in the community setting.
Could you provide a general overview of why you chose genitourinary oncology and what inspired you to enter this field?
Dr. Fleming: During my fellowship, I decided to specialize in genitourinary oncology due to the influence of 2 exceptional mentors and role models, Dr. Kevin Kelly and Dr. Howard Scher. Dr. Kelly was my initial mentor at Memorial Sloan Kettering, where I underwent a 3-year program focusing on GU Oncology. What made Dr. Kelly a great mentor was his approachability, intelligence, and his transparency on sharing his insights in the field of GU Oncology. He was a valuable resource for me. After my second year, Dr. Kelly left Memorial Sloan Kettering for additional pursuits, but I have been able to continue to collaborate with him in research and program development. While I was initially disappointed, it turned out to be a positive, a blessing in disguise since I got a chance to work more directly with Dr. Scher.
Dr. Scher was the long-term chair of the Genitourinary Program at Memorial Sloan Kettering, specifically the head of the Prostate Program. His incredible mind and visionary approach taught me a great deal about strategy on how to build something bigger than yourself and for the benefit of others. Both of these mentors have had a significant impact on my career, and I consider myself a disciple of both of them. Dr. Scher’s recent recognition by his peers as a Giant of Cancer Care underscores his longstanding contribution to prostate cancer care. So, in essence, it was these mentors who inspired my journey into genitourinary oncology.
Furthermore, my personal experience with my father’s prostate cancer diagnosis played a crucial role in my choice of specialty. Witnessing my father’s battle with prostate cancer, and ultimately losing him to the disease, made me a better physician because I could relate to my patients and their families on a deeper level. This personal connection drives me to bring the latest advancements to my patients.
I take great pride in being a community physician while also providing state-of-the-art treatments to the majority of cancer patients who are treated in their local communities. Our team at Virginia Oncology Associates also brings clinical trials to our patients, advancing the field of prostate cancer treatment.
How did your great mentorship and experiences early in your career lead you down the path of developing and investigating enzalutamide in prostate cancer?
Dr. Fleming: My journey with enzalutamide is a memorable one. At the time, my wife and I had just welcomed our daughter, and my wife was still working remotely. I had heard about this promising new drug and had seen impressive early data. A phase 3 trial was being developed to further study this drug. The American Society of Clinical Oncology meeting was in Florida that year, and I remember not asking my wife but rather telling her that I needed to attend that meeting to facilitate being able to bring this groundbreaking drug to my patients. It was a difficult conversation, but I felt a strong conviction that I had to go.
I met with Muhammad Hirmand from Medivation, essentially begging him to participate in the study as an investigator. I recall one patient, a teacher who had significant swelling in his legs from his disease, and I convinced him to participate in the trial even though he might end up with a placebo instead of the enzalutamide. Within a week, the swelling in his legs disappeared, and it was a moment that affirmed my commitment to bringing novel treatments closer to home for our patients. Enzalutamide became a game-changer for many patients offering a chance of longer survival with less toxicity, and I am proud to have been a part of its development.
Subsequently, we conducted another study combining docetaxel and enzalutamide, partnering with my mentors at Memorial Sloan Kettering. This was also an exciting study showing the safety and effectiveness of synergistic drug combinations which served as a proof of principal that we commonly employ today in prostate cancer treatment. I witnessed firsthand the benefits it brought to patients and the ability to do a phase 1 study within VOA.
So, my involvement in the development and investigation of enzalutamide was a pivotal moment in my career, and it demonstrated what community oncologists can achieve when it comes to clinical trials and research.
Can you elaborate on any ongoing initiatives or early-stage drug development programs that you are involved in and find particularly exciting?
Dr. Fleming: There are several exciting developments in the field of prostate cancer treatment. Lutetium therapy, also known as Pluvicto, stands out as a significant advancement. This prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical has shown great promise, and we are bringing targeted therapy like this to our community.
We are also exploring other therapies, such as flotufolastat, which involves PSMA PET imaging. The early results from this research have been impressive, and improved imaging technologies are crucial for early diagnosis and treatment planning.
Looking ahead, we are investigating bispecific T-cell engager (BiTE) therapy and CAR T-cell therapy for prostate cancer. These immunotherapies show potential in solid tumor treatment. Additionally, we are exploring protein degraders, like PROTACs, as a new approach to prostate cancer therapy. These initiatives aim to improve patient outcomes by targeting specific genetic mutations and amplifications.
Moreover, we are working on moving treatment earlier in the course of the disease. Currently we are investigating the use of Lutetium before chemotherapy. Our goal is to provide patients with the latest and most effective treatments closer to home, allowing them to benefit from cutting-edge therapies.
Our collaboration with the Sarah Cannon Research Institute is an opportunity to expand our research program and offer a larger portfolio of clinical trials to patients closer to home. This will allow folks that might otherwise not have access to clinical trials typically reserved for large academic centers. We believe these opportunities will be revolutionary toward benefitting our patients.
Given the various avenues of research and treatment in prostate cancer, do you believe that novel therapies or repurposing existing therapies in earlier lines will have a more significant impact on patient outcomes in the near future?
Dr. Fleming: I believe that the future of prostate cancer treatment will involve a combination of novel therapies and repurposing existing ones in earlier lines of treatment. Early diagnosis, improved imaging, and genomic testing are essential components of this approach. By identifying cancer at an earlier stage and tailoring treatments to specific genetic profiles, we can make significant strides toward curing more patients.
Innovative therapies like BiTE therapy, CAR T-cell therapy, and lutetium therapy hold great promise and may become transformational in the field. However, we should not discount the importance of repurposing existing therapies in earlier treatment lines. These therapies have demonstrated efficacy and using them strategically can benefit patients by delaying disease progression and improving overall outcomes.
It is crucial to continue exploring both avenues—novel therapies and optimized use of existing treatments—in our quest to improve prostate cancer care and move closer to a cure. Additionally, raising public awareness and increasing participation in clinical trials are vital steps in advancing the field and providing patients with the best possible care.