Current State of Castration-Resistant Prostate Cancer
Published Online: December 23, 2013
Daniel P. Petrylak, MD
The Progression of Prostate Cancer to Castration- Resistant Disease
Prostate cancer (PrCa) is the most common cancer found among men in the United States and is the second-leading cause of death for American males. Statistical analyses have projected an estimated 238,590 cases of PrCa among US men in 2013 alone, with approximately 29,720 expected deaths in this population during 2013. In males, the probability of developing invasive PrCa increases with each decade of life, with a risk that rises from 1 in 37 males between 40 and 59 years of age to 1 in 8 males for those who are 70 years and older. Between birth and death, the probability of developing invasive PrCa is estimated to be 1 in every 6 US men.1 Improvements in the early detection of PrCa have led to a substantial reduction in the number of patients who are diagnosed with advanced stages of the disease. Increased rates of screening for levels of prostate-specific antigen (PSA) have led to a notable decline in late-stage diagnoses of PrCa. Analyses of data from the Surveillance, Epidemiology and End Results (SEER) database between 1992 and 2008 identified a 75% reduction in late-stage disease incidence. However, regardless of these improvements in early detection, PrCa continues to be a leading cause of mortality among US males, invariably due to the emergence of hormonerefractory, androgen-independent disease.1-4
Although many patients with PrCa experience disease control after primary therapy, 1 retrospective analysis of patients who had undergone prostatectomy after an initial instance of PrCA found that 34% of patients developed metastatic disease after a median of 5.4 years of follow-up.5 For those men whose disease recurs, the majority will relapse biochemically as evidenced by elevated PSA levels, but the use and timing of androgen deprivation therapy (ADT) for biochemical relapse is controversial.6 Although higher levels of PSA at baseline in a patient is indicative of greater risk for metastatic disease or subsequent disease progression, it should be noted that PSA remains an imprecise marker of risk.7 PSA alone may not predict the onset of metastatic disease. Also, other factors, such as PSA doubling time, patient life expectancy, and comorbidities, may often prescribe when hormonal therapy is utilized.
In patients with advanced disease, androgen deprivation blockade, which may be achieved pharmacologically or surgically, leads to the regression of metastatic disease in the majority of patients.8 With androgen blockade, patients with high-risk, locally advanced, or metastatic disease may experience long-term regressions in disease activity, but advanced PrCa virtually always progresses to castration-resistant PrCA (CRPC), which is also known as androgen-independent PrCa (AIPC).9 CRPC is clinically detected by recurring symptoms, a rise in PSA levels, progression in soft tissue disease, or progression on bone scan.10 A significant PSA elevation is typically defined as 3 consecutive rises over its lowest point following treatment.9 This rise in PSA occurs in the context of the patient having castrate levels of serum testosterone (<50 ng/dL) following a withdrawal of antiandrogen therapies for at least 4 weeks, despite secondary hormonal manipulations and/or radiologic evidence for disease progression.9
The management of CRPC presents a number of difficult clinical challenges. Notably, systemic therapeutic options for this stage of PrCa have been very limited in the past. Historically, for patients with PrCa who failed hormonal therapy, traditional treatments were only approved for, and used primarily to provide, symptomatic benefits.9 These therapies included: (1) bisphophonate agents to protect the skeletal integrity in patients with bony metastases; (2) secondary hormonal manipulations, such as ketoconazole combined with hydrocortisone; (3) the addition of antiandrogen chemotherapy; and (4) beta-emitting radioactive isotopes.9 Over the past decade, however, there have been substantial improvements in the understanding of the biological and genetic bases for the progression of PrCa. This increased comprehension is partially attributable to the development of high-throughput genomic, transcriptomic, and proteomic technologies.9 The mechanisms of androgen independence in CRPC have been researched extensively, including pathways that are mediated by the androgen receptor (AR), as well as the pathways that bypass this receptor.9,11,12 In addition, the mechanisms that are common to all cancer types underlying malignant proliferation, angiogenesis, metastatic spread, and the avoidance of immune surveillance also play major roles in the progression of PrCa to castration-resistant disease. With all these potential targets, new mechanisms of action, treatment pathways, and novel therapies have been investigated to better target therapy for CRPC in efforts to potentially retard disease progression and to further improve patient outcomes.9
Mechanisms Surrounding Development of CRPC and Metastatic Disease
Androgen Receptor Signaling and CRPC
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