Approved Therapeutic Options
Currently, mCRPC remains incurable, and many treatment options are palliative in nature. However, the treatment landscape of mCRPC is expanding both in broad-spectrum and targeted therapies that are likely to positively impact overall survival rates within the next decade.
This expansion began with docetaxel, which, in 2004, was the first therapy to provide improved survival rates to patients with mCRPC. However, many patients develop resistance.15 To combat this issue, 5 new agents have received approval by the US Food and Drug Administration (FDA) to treat mCRPC since 2010 (abiraterone acetate, enzalutamide, cabazitaxel, radium-223, and sipuleucel-T).16
Some of these agents may be administered in combination with steroids, such as prednisone, which has been shown to decrease testosterone levels and reduce tumor growth as well as counteract adverse events (eg, nausea, allergic reactions, inflammation, pain).17,18
Recently FDA-approved agents that target the cancer and host compartments are discussed below and are also illustrated in Fig 1.
(To view a larger version of Figure 1, click here.)
Targeting Metastatic Castration-Resistant Prostate Cancer Cells
One of the defining measures of mCRPC is resistance to androgen deprivation. The mechanism of castration resistance is not fully understood but inroads have been made.
For example, prostate cancer cells circumvent castration by overexpressing and increasing the sensitivity of the AR to residual androgens, acquiring AR gene mutations that lead to functional gain or promiscuous ligand interactions, splice variants resulting in constitutive AR activation, and post-translational modifications affecting the stability, localization, and activity of the receptor.19
Alternative methods utilized by prostate cancer cells to synthesize dihydrotestosterone (DHT) have also been shown to circumvent androgen deprivation methods.20-22 Efforts to target DHT synthesis have resulted in FDA-approved androgen deprivation therapy (ADT) options.
Abiraterone acetate is one such option that works by inhibiting the activity of the CYP17A1 enzyme, thereby preventing androgen synthesis. Abiraterone has improved the overall survival and radiographic progression-free survival rates of men with mCRPC.23,24
Another therapeutic strategy for preventing androgen utilization by mCRPC cells is to directly target the AR with reagents such as flutamide, nilutamide, and bicalutamide. Enzalutamide was recently approved for the treatment of mCRPC in a postdocetaxel setting without the administration of corticosteroids.25,26
Enzalutamide has a superior affinity to the AR compared with other AR antagonists and works by preventing nuclear translocation of the receptor, DNA binding, and recruitment of coactivators of the AR to increase overall survival rates and delay the onset of SREs.27-29
Results of a phase 3 trial demonstrated enzalutamide activity in patients naive to chemotherapy, and FDA approval of enzalutamide as a first-line therapeutic option for mCRPC may be on the horizon.30
A list of approved therapies for the treatment of mCRPC appears in Table 1.15,23,24,27,28,31-36
Table 1. Approved Therapies for the Treatment of Metastatic Castration-Resistant Prostate Cancer
|Abiraterone acetate||CYP17A1||Reduces circulating testosterone levels23,24|
|Cabazitaxel||Microtubules||Microtubule stabilization, interrupts cell cycle31|
|Denosumab||RANKL||Decreases bone resorption34|
|Docetaxel||Microtubules||Microtubule stabilization, interrupts cell cycle15,36|
|Enzalutamide||AR||AR antagonism, prevents signaling27,28|
|Sipuleucel-T||Ex vivo activation of PBMCs via GM-CSF and PAP||T-cell activation32|
|Zoledronic acid||Osteoclasts||Decreases bone resorption33|
|Note: AR = androgen receptor, GM-CSF = granulocyte-macrophage colony-stimulating factor, PAP = prostatic acid phosphatase, PBMC = peripheral blood mononucleated cell, RANKL = receptor activator of nuclear κB ligand.|
In addition to ADT strategies, taxane-derived chemotherapies are commonly used to treat mCRPC. Docetaxel was the first therapy to demonstrate a beneficial effect on overall survival rates accompanied by improved quality of life for men with mCRPC, and it has since become the standard therapy for mCRPC.15,36
Cabazitaxel is a more recent derivative of the taxoids that has shown increases in overall survival rates, improvements in progression-free survival rates, and improved PSA response rates in men with mCRPC.31,37 Cabazitaxel-associated toxicities were minor, leading to the FDA approval of the therapy for the treatment of patients with mCRPC after treatment with docetaxel.38