Immuno-Oncology and PARP Inhibition - November 2020

Three topics dominate this issue: the current status of the Provenge (sipuleucel-T) vaccine, the status of other immunotherapy techniques under development, and the use of poly ADP ribose polymerase (PARP) inhibitors. Behind these specific topics, this issue illustrates how the treatment paradigm has been shifting. Prostate cancer treatment selection has traditionally been done without knowledge of the specific molecular characteristics of a given patient’s cancer. The revolution in molecular biology increasingly allows a clinician to test for these molecular changes and then tailor the treatment to the patient and his cancer. These techniques are also providing other benefits. We now know some of the mechanisms that allow prostate cancer to evolve resistance to existing treatment options. This knowledge then leads to new drug development or new approaches to immunotherapy. One example of this is the new generation of antiandrogens, starting with Zytiga (abiraterone acetate) and Xtandi (enzalutamide).

PARP inhibitors are a new class of drugs that are a direct outcome of research on molecular changes that have a profound impact on prostate cancer biology. This story starts with the discovery of gene mutations associated with familial breast cancer: breast cancer type 1 and type 2 susceptibility proteins. These are abbreviated as BRCA-1 and BRCA-2. These two proteins are involved in DNA repair, and when they are inactivated by mutations, DNA repair is less efficient, leading to a greater likelihood that cancercausing mutations will develop. In cells with BRCA-1 or -2 mutations, some residual DNA repair does take place using the PARP. This allows sufficient DNA repair for the cancer cell to survive. If PARP is also inactivated, the cancer cell dies. This led to the development of drugs to inhibit PARP. These drugs proved to be more useful in BRCA-1 or -2 mutant ovarian rather than breast cancer and are now standard in the treatment of ovarian cancer.

Studies have shown that men who inherit mutationally inactivated BRCA-2 are at increased risk of developing prostate cancer. These cancers tend to be very aggressive, rapidly becoming resistant to hormonal therapy and are associated with short survival. BRCA-2 mutations are relatively uncommon in men with newly diagnosed prostate cancer, but they become more common as the cancer progresses through standard treatments. Clinical trials have shown that PARP inhibitors have useful activity against prostate cancer that has mutations in BRCA-2 and other DNA repair mutations. As a result, PARP inhibitors are now approved for the treatment of prostate cancer.

As discussed by several interviewees, there are reasons to think that combining PARP inhibitors with immunotherapy might prove beneficial. This issue also contains information about which patients are most likely to benefit from Provenge (sipuleucel-T).

In general, patients with less extensive disease and a slower prostate-specific antigen (PSA) doubling time tend to do better. Finally, a range of potentially new approaches to immunotherapy of prostate cancer are discussed. If you fit the eligibility requirements, you might want to consider entering one of the clinical trials.

Charles E. Myers, Jr., MD

Link to November's Prostatepedia