Daniel J. George, MD

Daniel J. George, MD, professor of medicine and surgery, and member, Duke Cancer Institute, discusses the changing treatment landscape in prostate cancer.

Within the past decade, hormonal therapy, particularly androgen deprivation therapy, has been the focus of treatment for patients with metastatic prostate cancer. Over the past few years, that landscape has changed, with data showing the clinical benefit of docetaxel, abiraterone acetate (Zytiga), apalutamide (Erleada), and enzalutamide (Xtandi) upfront in the metastatic hormone-sensitive setting.

These findings have opened the door to explore additional cytotoxic approaches with radiopharmaceuticals, such as radium-223 dichloride (Xofigo), docetaxel, and cabazitaxel, or other targeted approaches, such as prostate-specific membrane antigen (PSMA)—directed therapy in the post-androgen receptor and -chemotherapy settings. Some of these approaches could end up being used in the curative setting, which would result in a paradigm shift in the advanced setting, concludes George.

Videos

Daniel J. George, MD, discusses the changing treatment landscape in prostate cancer.

Dr. George on the Changing Treatment Landscape in Prostate Cancer

Daniel J. George, MD, professor of medicine and surgery, member, Duke Cancer Institute, discusses investigational agents downstream of the androgen receptor (AR) in advanced prostate cancer.

There is still a lot of work that needs to be done in order to understand how to pair agents downstream of the AR with other treatments, says George. However, such combinations could obviate the need for a sequential approach, he adds. Several novel mechanisms of action are under investigation, including transcription factors, such as EZH2 and DNA-dependent protein kinase catalytic subunits, agents which could modulate resistance to the AR. In addition, PARP inhibitors are under evaluation in selected patient populations.

Investigators are also evaluating novel ways to target the AR besides just the ligand domain, says George. Additional therapeutic classes under investigation include immunotherapy and PSMA-targeted strategies, such as bispecific antibodies and radiopharmaceuticals.

Daniel J. George, MD, discusses investigational agents downstream of the androgen receptor in advanced prostate cancer.

Dr. George on Investigational Agents Downstream of the Androgen Receptor in Prostate Cancer

Daniel J. George, MD, professor of medicine and surgery, member, Duke Cancer Institute, discusses the use of radium-223 dichloride (Xofigo) in prostate cancer.

Radium-223 operates through a novel mechanism and has shown a reduction in the risk of progression or death of approximately 30% versus placebo in patients with metastatic castrate-resistant prostate cancer. Although the drug has shown a benefit in overall survival in a historically difficult-to-treat patient population, it has not been shown to affect prostate-specific antigen response or imaging response. As such, it has been difficult to employ in practice, says George.

Moreover, data from the phase III ERA-223 trial, which were presented at the 2018 ESMO Congress, pointed to the added complication of risk of fractures. In the trial, chemotherapy-naïve patients with mCRPC received abiraterone acetate (Zytiga), prednisone, and radium-223, or abiraterone and prednisone alone. Patients who received radium-223 had a higher rate of fractures than those who received abiraterone and prednisone alone. This was a new finding, says George, suggesting a potentially toxic synergy between abiraterone, prednisone, and radium-223 in a less heavily pretreated patient population. Now, there is a warning against the use of radium-223 in combination with abiraterone. However, because bone metastases lead to increased risk of mortality, George states that radium-223 can be used as monotherapy to lessen the burden of metastatic disease.

Dr. George on the Use of Radium-223 in Prostate Cancer

Daniel J. George, MD, professor of Medicine and Surgery, member, Duke Cancer Institute, discusses the promise of PARP inhibitors in prostate cancer.

PARP inhibitors hold a lot of promise in patients with homologous recombination deficiency (HRD), particularly those who harbor alterations in 

. Other HRD alterations that may be important include 

, although the data in this space are less clear, says George.

Some of these mutations are seen at the germline level; therefore, screening patients with metastatic disease for these alterations is recommended. More importantly are tests that can detect somatic alterations, adds George. Although these tests are encouraged, they are not always feasible. In addition to tumor biopsies, cell-free DNA may be another way to assess the biology of a patient’s tumor.

PARP inhibitors are likely to have a role in the treatment of patients with HRD, whether as single agents or in combination, says George. The question is whether they will play a role in patients without HRD. Synthetic lethality may be a way of enabling this, either with radiation or immunotherapy. Trials are ongoing and, if positive, may broaden the accessibility of these agents.

Author | Daniel J. George, MD

Articles

New content coming soon, please check back later.