Abstract and Introduction
Abstract
Background A paucity of therapeutic options is available to treat men with metastatic castration-resistant prostate cancer (mCRPC). However, recent developments in our understanding of the disease have resulted in several new therapies that show promise in improving overall survival rates in this patient population.
Methods Agents approved for use in the United States and those undergoing clinical trials for the treatment of mCRPC are reviewed. Recent contributions to the understanding of prostate biology and bone metastasis are discussed as well as how the underlying mechanisms may represent opportunities for therapeutic intervention. New challenges to delivering effective mCRPC treatment will also be examined.
Results New and emerging treatments that target androgen synthesis and utilization or the microenvironment may improve overall survival rates for men diagnosed with mCRPC. Determining how factors derived from the primary tumor can promote the development of premetastatic niches and how prostate cancer cells parasitize niches in the bone microenvironment, thus remaining dormant and protected from systemic therapy, could yield new therapies to treat mCRPC. Challenges such as intratumoral heterogeneity and patient selection can potentially be circumvented via computational biology approaches.
Conclusions The emergence of novel treatments for mCRPC, combined with improved patient stratification and optimized therapy sequencing, suggests that significant gains may be made in terms of overall survival rates for men diagnosed with this form of cancer.
Introduction
Prostate cancer is the second most common cancer in American men with approximately 233,000 newly diagnosed cases in 2014. With an aging population, the incidence of prostate cancer is likely to continue to increase. Patients whose disease is detected at an early stage benefit from a range of treatment strategies, including radiotherapy and prostatectomy, with survival rates near 100%. However, the clinical reality is that many men present with advanced stages of the disease. Currently, the main treatment option for men with advanced cancer is hormone therapy. Historic contributions from Huggins and Hodges in 1941 revealed that removing androgens could inhibit the progression of prostate cancer. These early observations paved the way for the development of androgen-deprivation therapy — either surgically or chemically — which has remained the standard treatment for men with advanced disease for the last 70 years. Despite the initial response to androgen deprivation for most men, the disease typically progresses to a castration-resistant state within 18 to 24 months.
Castration-resistant prostate cancer (CRPC) is defined by disease progression that, despite chemical castration, is often indicated by rising levels of prostate-specific antigen (PSA). The development of resistance to hormonal intervention and why the disease progresses is not fully understood, although some mechanisms have been demonstrated, with the majority focusing on the continued androgen receptor (AR) activity in addition to TMPRSS2/ERG fusion, PTEN, Nkx3.1, and EGR1. As the disease progresses, the CRPC ultimately metastasizes (mCRPC). Patients with mCRPC have a poor prognosis and a predicted survival rate of fewer than 2 years from the initial time of progression, comprising a large portion of the 30,000 prostate cancer-related deaths per year. Currently, mCRPC is an incurable disease and represents a major clinical hurdle.
Prostate cancer preferentially metastasizes to bone. As the disease transitions from castration sensitive to castration resistant, the incidence of bone metastasis increases, with more than 90% of patients with mCRPC developing bone metastases. Patients with mCRPC who are symptomatic are at a high risk for skeletal-related events (SREs), including spontaneous fracture and spinal cord compression, that are a source of significant pain and decreased quality of life. Pain from the metastases is a major component of the disease and is an important aspect to be considered regarding a patient's treatment regimen. Depending on the level of pain, medications ranging from ibuprofen to morphine are prescribed. Because prostate to bone metastases are primarily bone-forming sclerotic lesions, bone scanning using technetium-99m is often preferred for diagnosis due to the incorporation of the radionuclide tracer into regions of new bone formation by osteoblasts. Magnetic resonance imaging (MRI) and positron emission tomography (PET)/computed tomography (CT) are also used for detection. A trial comparing 18F–sodium fluoride PET/CT, 18F-fluorodeoxyglucose PET/CT, MRI, and technetium-99m identified strengths for each modality. However, the ability to detect occult or micrometastases less than 5 mm remains a current limitation for each imaging technique.