According to the American Cancer Society, prostate cancer is the most frequently diagnosed cancer among men, other than skin cancer, in the United States. Approximately 221,000 new cases of prostate cancer are expected to be diagnosed in the United States this year, and approximately one in seven men will be diagnosed with prostate cancer during his lifetime.
Advances in the screening and diagnosis of prostate cancer have facilitated the early detection of prostate cancer. When detected in its early stages, prostate cancer is curable in a majority of men. In some cases, however, prostate cancer recurs and therapeutic intervention is required. Despite the approval of new drugs for the treatment of prostate cancer, there remains a significant unmet need for men who do not respond to, or who cannot tolerate, current therapies. The American Cancer Society estimates that in the United States alone 28,000 men are expected to die of prostate cancer this year.
Treatment of Advanced Prostate Cancer
Patients who are diagnosed with prostate cancer are typically treated with surgery and/or radiation therapy. Patients whose prostate cancer recurs following those treatments are considered to have advanced prostate cancer.
The growth and survival of prostate cancer tumors rely primarily on the functioning of the androgen receptor signaling pathway. This pathway is activated by the binding of androgens, such as testosterone and DHT, to the androgen receptor in prostate cancer cells. The first line of treatment for prostate cancer involves androgen deprivation therapy with hormones that reduce testosterone levels to those that are similar to the levels found in men who have been surgically castrated.
While patients with advanced prostate typically respond to androgen deprivation therapy, nearly all patients experience a recurrence of tumor growth over time. Patients whose tumors grow despite the reduction of testosterone to castrate levels are considered to be castration resistant. Historically, the next line of treatment for patients with castrate-resistant prostate cancer (CRPC) has been chemotherapy. Recently, however, several new drugs have been approved to treat CRPC. Despite these advances in the treatment of CRPC, there remain a number of mechanisms by which CRPC cells become resistant to these new therapies and cause the tumor to grow, or for which these new therapies have no impact.
Over the past two years, the medical community’s understanding of the most significant resistance mechanisms to currently-available CRPC therapies has matured. In a growing number of published studies, C-terminal loss, or the truncation of a portion of the androgen receptor, has emerged as a primary driver of resistance. The AR-V7 splice variant is the most common form of C-terminal loss.
Efstathiou E et al, Eur. Urology, 2014; Antonarakis E et al, AACR, ASCO, ESMO, NEJM, 2014; Efstathiou E et al, ASCO, 2014; Scher H et al, ESMO, 2014