by Ashley Ross, MD, PhD
The prostate is a hormonally regulated organ and prostate cancer is reliant on androgen receptor signaling for growth. The treatment of advanced prostate cancer has thus traditionally focused on the inhibition of androgen signaling (for example through blockade of the androgen receptor, or inhibition of testosterone production). In the majority of cases, however, the prostate cancer will adapt to low androgen states and become castrate-resistant.
Newer therapeutics (such as enzalutamide, apalutamide, and abiraterone) which further suppress hormonal signaling prolong survival for men and are transiently effective when men become castrate resistant but clearly more options are needed. With this in mind, investigators have been developing novel therapies for castrate-resistant disease.
In May of this year, two PARP inhibitors, olaparib, and rucaparib were FDA approved for the treatment of castrate-resistant prostate cancer in men with BRCA mutations. These men with BRCA mutated tumors, however, encompass the minority of the castrate-resistant population.
In order to provide options for more men, Mary Crowley Cancer Research and other institutions are continuing to carry out clinical trials. Three ongoing trials at Mary Crowley highlight promising therapeutic approaches. One approach is to inhibit pathways that are commonly over-active in advanced prostate cancer beyond androgen signaling. One such pathway is the PI3K-AKT pathway which regulates growth and survival. An ongoing trial uses afuresertib (an AKT inhibitor) in combination with androgen axis inhibitors to kill resistant prostate cancer.
Another effort looks to potentially reverse the cancer’s resistance to androgen axis therapies. In this trial, the drug tazemetostat is being used. Tazemetostat blocks EZH2 which plays a role in DNA packaging and accessibility in the cell. Tazemetostat may help reverse the resistance of advanced prostate cancer to androgen inhibitors.
Finally, yet another effort works to capitalize on the overexpression of Prostate-Specific Membrane Antigen (PSMA) on prostate cancer cells. In this study, an antibody type molecule links to PSMA and attracts immune cells to the cancer with the hopes of mounting an immune response against the man’s prostate cancer.
These trials provide exciting opportunities for men with advanced prostate cancer and, along with the recent drug approvals, speak towards how precision medicine and recent molecular advances are striving to improve prostate cancer treatment.