Treatment of metastatic castration resistant prostate cancer (mCRPC) has progressed throughout the years due to a number of advances in knowledge and understanding of the disease. Beginning with androgen deprivation therapy (ADT) as the standard of care due to the 1941 finding that prostate cancer regresses with androgen withdrawal, treatment has continually focused on androgen receptors as targets for fighting mCRPC.
“Changing Paradigms in Management of mCRPC” highlights a shifting focus from ADT therapy by either surgical or medical castration to inhibit steroid biosynthesis. Castration is proven to be effective due to the resulting low levels of serum testosterone for some individuals, but for others who have mCRPC, prostate cancer death is common. Inhibiting steroid biosynthesis sidesteps the fact that some prostate cancer cells amplify androgen receptor genes and become more sensitive to the low levels of circulating testosterone.
A common target for inhibiting steroid biosynthesis is CYP17, a cytochrome P450 enzyme that enables two reactions required for sex steroid synthesis. Ketoconazole, a non-steroidal imidazole anti-fungal agent that inhibits CYP17 has been used off-label for treating prostate cancer as a second-line hormonal therapy since the 1980s. Although prostate specific antigen (PSA) levels fall in patients taking ketoconazole, studies show no survival benefit of treatment and identify several adverse events of therapy.
To improve upon the available treatment options, two new hormonal therapy agents in the end stages of development show efficacy in fighting mCRPC. Abiraterone acetate (Zytiga), which is approved by the Food and Drug Administration (FDA) suppressed circulating androgen levels during phase 1, 2, and 3 clinical trials when administered at a dose of 1000 mg/day.
The other, enzalutamide (MDV3100, or Xtandi) competitively inhibits androgen binding to androgen receptors, preventing stimulation of prostate cancer cells. As a second-generation androgen receptor antagonist, it binds more strongly to androgen receptors that do first-generation antagonists flutamid and bicalutamide. In the AFFIRM TRIAL, 1,199 men with mCRPC were treated with enzalutamide, and treatment led to positive benefits on survival and time to first metastasis. During the PREVAIL trial, 1717 mCRPC patients were treated and showed additional benefits of treatment, leading to submission for FDA approval.
At least three other steroid-related inhibitors are under development in clinical trials. Orteronel (TAK 700), ARN509, and Galeterone (TOK-001) disrupt steroid signaling pathways and steroid biosynthesis. Preliminary results of trials indicate patient tolerability of treatment, but more data are required to definitively establish efficacy of treatment.
Finally, as the field is becoming more educated in the workings of prostate cancer, existing cancer therapies can be tuned to specific cancer cases. The authors recommend abiraterone as a treatment for chemotherapy naive mCRPC and abiraterone or enzalutamide for post chemptherapy-docetaxel-treated patients. With a handful of effective agents available for mCRPC patients, further studies to determine optimal drug combinations and doses will improve treatment.