The Shifting Prostate Cancer Treatment Paradigm

In the last 2 years, the FDA has approved several new active metastatic prostate cancer therapies. This progress was made after researchers discovered that the available androgen deprivation therapies (ADT) had failed patients and that castration-resistant prostate cancer (CRPC) is not actually resistant to hormonal manipulation. Rather, ADT reduces levels of circulating hormones by 95%, but only by 75% within the prostate. Advanced prostate tumors are adept at making their own testosterone. Therefore, tumors seemingly resistant to androgen deprivation remain dependent on androgen receptor signaling for their growth—these tumors still rely on hormone signaling.

About 70 years ago, researcher Charles B. Huggins discovered that male hormones (androgens) are important for the growth and survival of prostate cancer tumors. In 1966, Huggins was awarded the Nobel Prize for Physiology or Medicine for his work on using hormones to control prostate cancer. In the last 10 years, studies have shown that castrate-resistant prostate tumors can continue to make their own hormones and can also increase the expression of androgen receptors on prostate cancer cells. This continued hormone signaling allows for continued tumor growth and cancer progression.

New oral androgen receptor signaling therapies have taken advantage of this latest research, targeting either hormones themselves or their receptors. These drugs provide new opportunities for patients who, just a few years ago, would have run out of treatment options.

Abiraterone acetate was initially approved first for treating chemotherapy-refractory metastatic castrate-resistant prostate cancer (mCRPC). In December 2012, it was approved for treatment of CRPC in patients who have not been previously treated with chemotherapy. Abiraterone acetate blocks an enzyme that facilitates the synthesis of a precursor of testosterone in both the prostate tumor and the adrenal glands. Testing abiraterone in a premetastatic setting is in the works.

Another recently approved agent for mCRPC after treatment with chemotherapy, enzalutamide (MDV3100), has a different mechanism. Enzalutamide works well in patients whose prostate tumors express higher levels of androgen receptors. The drug binds to the androgen receptors, preventing their interaction with hormones made by the prostate cancer cells. A phase III clinical trial is currently testing the role of enzalutamide in mCRPC patients who have not yet been treated with chemotherapy.

Abiraterone and enzalutamide are already being tested in combination. An ongoing phase I trial aims to understand the potential drug-drug interactions and whether the combination of both therapies results in better tumor control than a single therapy treatment.

Other androgen pathway therapies are still in development. ODM-201, which targets the androgen receptor, is in phase II for mCRPC patients. Orteronel is an oral, nonsteroid inhibitor of androgen synthesis with a similar mechanism as that of abiraterone. A phase III trial in mCRPC patients is underway.

Metastatic prostate cancer is complex, and these agents, while an improvement, are not curing advanced cancer patients. Researchers would like to test these agents earlier in the course of metastatic disease—in the adjuvant or neoadjuvant setting or even in combination with surgery—to see if earlier treatment could boost cure rates. Another question already being asked by clinicians is which agent, abiraterone or enzalutamide, should be used first. Only a clinical trial can address issues such as crossresistance or enhanced sensitivity of one of the therapies after another. The answers could further help researchers understand how prostate cancer cells evolve and develop resistance.