Prostate cancer is a confounding disease. It demonstrates a remarkable spectrum of tumor behavior. Low-risk cancer may be indolent and take 20 years to cause death.
Advanced prostate cancer grows rapidly, causing local symptoms of urinary obstruction and hematuria, then distant symptoms from enlarging pelvic and retroperitoneal lymphadenopathy, painful bony metastases, and diffuse systemic metastases. Patients with advanced disease typically suffer from difficult-to-relieve symptoms before succumbing to the disease.
Prostate cancer remains the most common non-skin cancer for men in this country and is persistently the second-leading cause of cancer death. According to the Centers for Disease Control and Prevention, in 2009 — the most recent year for which statistics have been reported — the number of men diagnosed with prostate cancer was 206,640, and 28,088 men died from the disease.
With prostate-specific antigen (PSA) screening, most men diagnosed with prostate cancer present with early-stage disease. In fact, only 4 percent present with distant disease. Prior to the PSA era, up to 30 percent of men diagnosed with prostate cancer presented with advanced disease. If PSA screening is abandoned, models predict we will see more men presenting with advanced prostate cancer again. Men with early-stage prostate cancer treated with prostatectomy or radiation generally achieve high cure rates. However, more than 10 percent of men eventually have a recurrence. When cancer relapses or presents with advanced-stage disease, the treatment strategy is markedly different. Unfortunately, advanced prostate cancer is lethal. Discoveries from the past decade are now able to extend life expectancy.
Prostate cancer growth is primarily regulated by androgens. Androgen deprivation therapy (ADT) can either induce apoptosis or cause arrest of the cell cycle at G1 phase. Therefore, ADT is the backbone of treatment for advanced prostate cancer. Tragically, prior to 2004, the most important discovery in the management of advanced prostate cancer was reported in 1941, when Huggins and Hodges described how orchiectomy prolonged life expectancy and decreased pain in metastatic prostate cancer. Currently, ADT is most commonly achieved by administering injections of luteinizing hormone-releasing hormone (LHRH) agonists or antagonists, although surgical castration is another option. Regardless, ADT does not cure prostate cancer. It improves survival, decreases symptoms and decreases the burden of disease, but it can be seen as only a temporary refuge. On average, men are on ADT for 18–24 months before progressing to castration-resistant prostate cancer (CRPC). Once CRPC has developed, average survival is nine to 22 months.
Traditionally, the treatment of CRPC has consisted of continuing ADT and adding androgen receptor blockers, estrogens or inhibition of adrenal androgen synthesis via ketoconazole, with most patients not responding to treatment. In the early 2000s, it was found that docetaxel-based chemotherapy prolonged life by three months. However, not all patients can tolerate systemic chemotherapy.
Sipuleucel-T (Provenge), a therapeutic cancer vaccine, was approved in 2010 for the treatment of metastatic, minimally symptomatic CRPC. A patient’s own antigen-presenting cells are harvested via leukopheresis, incubated with prostatic acid phosphatase (PAP), then infused intravenously. PAP is present in most prostate cancer cells. The vaccine stimulates the patient’s immune system against prostate cancer cells containing PAP. The IMPACT trial served as the basis of Food and Drug Administration approval and showed a 4.1-month survival advantage. This trial was analyzed on an intent-to-treat basis, utilizing a crossover in the placebo arm for patients who had disease progression. If we consider the results for patients who never received the medication compared with those who received it initially, the survival advantage is eight to nine months.
The next two new treatments challenge our understanding of how CRPC develops. It has previously been thought that CRPC grew independent of androgens; however, advanced prostate cancer cells can synthesize androgens themselves, overexpress androgen receptors (AR) and demonstrate altered androgen-receptor signaling.
Abiraterone acetate (Zytiga), an oral medication, potently inhibits the steroidogenesis pathway by inhibiting CYP17-hydroxylase and C17,20-lyase, effectively reducing the production of sex hormones throughout the body. Zytiga was first approved in 2011 for CRPC that progressed after docetaxel-based chemotherapy, showing a four-month survival advantage. In January 2013 it was subsequently approved for use in metastatic HRPC prior to chemotherapy. It is also well-tolerated, with the most common side effects being hypertension, hypokalemia or edema in less than a third of patients.
Enzalutamide (Xtandi) is a potent second-generation oral AR antagonist. It works on the AR through three distinct mechanisms: irreversible competitive binding to AR, inhibition of AR nuclear translocation and AR interaction with nuclear DNA. It was approved for use in metastatic HRPC after chemotherapy in August 2012, after demonstrating a five-month survival advantage (18 versus 13 months). Studies are maturing regarding its use prior to chemotherapy, which will likely be approved in the near future.
The multiple treatments approved for CRPC within the past three years are providing hope and extending quality and quantity of life for men who had few options. There are additional medications in the various phases of clinical trials. The outlook for treatment of advanced prostate cancer has never been more promising.
Gregory F. Byrd, MD, has been a member of the Wichita Urology Group since August 2007. He received his medical degree from the University of Washington in Seattle.