Targeting the Microenvironment

Given the heterogeneity of mCRPCs and the likelihood of ADT/chemotherapy resistance, targeting the genet­ically stable host microenvironment supporting the mCRPC represents an attractive treatment approach. Immune evasion is a hallmark of cancer progression, and the goal of sipuleucel-T is to make mCRPC more visible to cytotoxic T cells.32,39

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Sipuleucel-T is an au­tologous immunotherapy approved for the treatment of asymptomatic or minimally symptomatic mCRPC.40 Sipuleucel-T harnesses the properties of the patient’s immune system by collecting peripheral blood mono­nuclear cells and activating them ex vivo by expos­ing them to a fusion protein consisting of prostat­ic acid phosphatase (PAP; commonly expressed by prostate cancer cells) and granulocyte-macrophage colony-stimulating factor.

Patients receive 3 separate infusions of the activated cells at 2-week intervals to generate PAP-expressing dendritic cells that activate T cells to recognize and eliminate PAP-expressing prostate cancer cells.32

Most mCRPCs arise in the bone matrix where they induce extensive bone remodeling by stimulating osteoblasts and osteoclasts. The process promotes the growth of the mCRPCs via the solubilization of bone matrix–sequestered growth factors, causing pain and SREs (eg, pathological fractures).

There­fore, preventing the interaction of cancer and bone has been a major focus of treatment for several de­cades.

Bisphosphonates, such as zoledronic acid, are reagents that can “stick” to bones undergoing remodeling; upon resorption by osteoclasts, they can induce apoptosis and limit the amount of can­cer-induced bone disease.41 In the clinical setting, zoledronic acid has demonstrated a benefit for pa­tients with mCRPC by delaying the time to SRE in­cidence.33

However, no increase in overall survival rates has been demonstrated. Receptor activator of nuclear κB ligand (RANKL) is a molecule critical for the maturation and activation of bone-resorbing os­teoclasts. Denosumab is a fully humanized monoclo­nal antibody that prevents RANKL interaction with the RANK receptor.42 For patients with bone mCRPC, a significant delay has been demonstrated in the time to first SRE compared with zoledronic acid.34

Evidence suggests that denosumab may have direct effects on tumor burden, particularly tumor cells expressing RANK.43,44 Furthermore, preclinical in vivo animal studies have highlighted the efficacy of docetaxel/ denosumab treatment in increasing median survival rates, suggesting that combination approaches with denosumab could enhance the overall survival rates of men with mCRPC.45

At the time of publication, the most recent agent to receive FDA approval for mCRPC is radium-223.46 The bone-seeking properties of radium-223 (and other similar radiopharmaceuticals) make it useful for the treatment of bone metastases. Although most radiopharmaceuticals emit ß particles, radium-223 emits α particles to deliver more localized radiation (<100 μm distance) to induce cell death via DNA damage.47

In a study of men with mCRPC previously treated with radiotherapy, radium-223 showed improved rates of overall survival, time to PSA progression, and reduced alkaline phosphatase levels (a measure of bone remodeling).35 In addition, radium-223 delays the time to first SRE.35 Previous radiopharmaceuticals used to treat mCRPC were effective at reducing pain alone. Therefore, radium-223 represents an important step forward for the field.46

Emerging Therapeutic Options

Despite the growing number of FDA-approved agents to treat mCRPC, room remains to improve upon the therapeutic options available to patients and clini­cians. For example, although approximately 50% of patients with mCRPC will respond to docetaxel, most patients develop resistance and disease progression within 1 year of beginning treatment.36

However, some treatments that target cancer and support the microenvironment are currently in clinical trials that have the potential to provide health care professionals with new therapeutic options to treat men diagnosed with mCRPC (see Fig 1). A list of these experimental therapies appears in Table 2.32,48-57

Table 2. Experimental Therapies for the Treatment of Metastatic Castration-Resistant Prostate Cancer

Drug Target Effect Study Results
Cabozantinib c-MET VEGF-R2 Inhibits tyrosine kinase activity Partial resolution of bone lesions, decreases number of CTCs, decreases pain51
Custirsen Clusterin Improves response to docetaxel Extended median survival, extends PFS, improves PSA declines52
Ipilimumab CTLA-4 T-cell activation Ongoing54,55
Nivolumab PD-1 T-cell activation Ongoing53
Orteronel CYP17A1 (17,20 lyase activity) Reduces circulating testosterone levels Decreases number of CTCs, improves radiographic PFS48,49
Prostvac-VF Delivery of PSA transgene T-cell activation Improves median survival32,56
Tasquinimod Thrombospondin S100A9 Antiangiogenic, reduces MDSC recruitment Improves median PFS, stable bone alkaline phosphatase levels50,57
Note: CTC = circulating tumor cell, CTLA = cytotoxic T-lymphocyte antigen 4, MDSC = myeloid-derived suppressor cell, PD-1 = programmed cell death 1, PFS = progression-free survival, PSA = prostate-specific antigen, VEGF-R2 = vascular endothelial growth factor receptor 2.


Similar to abiraterone acetate, orteronel inhibits CYP17A1 to reduce circulating levels of testoster­one. However, orteronel possesses specificity toward lyase activity, leaving the synthesis of adrenal corti­sol unaltered.17,20 Therefore, orteronel is less likely than abiraterone acetate to require the concomitant administration of corticosteroids.25,58

Phase 2 trials demonstrated a significant reduction in serum levels of PSA that led to 10 partial responses and 22 cases of stable disease in 51 patients.59 Decreases in circulat­ing tumor cells were also observed, thus serving as a further indication of efficacy.

Based on these positive data, phase 3 trials were initiated; however, the results of one of those phase 3 trials indicated that orteronel administered in combination with prednisone failed to significantly impact overall survival rates compared with placebo but did provide a benefit in radiographic progression free survival rates in both chemotherapy naive and postchemotherapy mCRPC.48,49