In this review, we focus on the testosterone/androgen receptor pathway that is being targeted with potent new agents; we also discuss other important alternative biologic pathways that have given rise to new therapeutics that may attenuate prostate cancer growth, survival, and propagation.
In the field of metastatic castration-resistant prostate cancer, a bevy of novel therapeutics have recently been proven to extend survival via distinct mechanisms of action. Although revolutionary, these recent developments have not led to improved cure rates, and resistance eventually develops. Thus, further exploration into the biologic mechanisms of resistance to these new agents in prostate cancer has been necessary. This has opened the door to the development of agents designed to manipulate alternative biologic targets. In this review, we focus on the testosterone/androgen receptor pathway that is being targeted with potent new agents; we also discuss other important alternative biologic pathways that have given rise to new therapeutics that may attenuate prostate cancer growth, survival, and propagation.
Approximately 2.5 million men in the United States are living with prostate cancer. Although survival has increased significantly in the past decade, more than 28,000 men die of metastatic castration-resistant prostate cancer (mCRPC) each year. Androgen deprivation in the form of castration, either medical or surgical, remains the backbone of prostate cancer treatment. Nevertheless, most prostate cancers eventually become resistant to traditional medical or surgical castration and require additional therapeutic interventions. Historically, secondary systemic treatments have included first-generation anti-androgens, adrenal steroid synthesis inhibition with ketoconazole, estrogenic agents, and docetaxel (Taxotere) chemotherapy. However, a clearer understanding of mechanisms of resistance to castration have led to the development of next-generation androgen synthesis inhibitors; androgen receptor (AR) signaling inhibitors; and agents targeting other dysregulated signaling pathways that promote prostate cancer cell proliferation, invasion, and survival. Many of these agents have contributed to improved survival in men with mCRPC, and the median survival for these patients is now approaching 3 years. This review will first discuss novel androgen synthesis inhibitors and AR signaling inhibitors, then focus on other targeted agents in development for the treatment of mCRPC.
The role of testosterone in the pathogenesis of prostate cancer has been well established since it was first described by Drs. Huggins and Hodges in 1941. In essence, androgen deprivation therapy (ADT) was one of the first molecular-targeted therapies in oncology. Few other cancers have therapies with such uniformly high initial response rates. Unfortunately, prostate cancer progression usually occurs despite initial castration, and mechanisms of resistance to castration have historically been thought to be independent of the AR signaling axis. However, overexpression of AR; androgen synthesis by prostate cancer cells; alterations in expression of coactivators and corepressors of AR signaling; and constitutively active, ligand-independent AR splice variants have all been implicated as potential mechanisms of castration resistance.[4-7] Two novel agents that address such resistance mechanisms have earned approval by the US Food and Drug Administration (FDA) in the last 2 years.
Abiraterone acetate (Zytiga) is a potent selective inhibitor of CYP17-hydroxylase and C17,20-lyase, enzymes necessary for the synthesis of androgens from steroid precursors. A phase I study in men with mCRPC demonstrated that treatment with abiraterone was well tolerated and led to reductions in dehydroepiandrosterone sulfate (DHEA-S) and testosterone to near undetectable levels, resulting in significant decreases in prostate-specific antigen (PSA) levels, even in some patients who had received prior ketoconazole. The COU-AA-301 phase III trial involved a 2:1 randomization of men with mCRPC who had previously received docetaxel chemotherapy to abiraterone 1,000 mg/day with prednisone 5 mg bid (n = 797), or placebo with prednisone 5 mg bid (n = 398). Abiraterone significantly prolonged overall survival (OS) compared with placebo (median, 14.8 vs 10.9 months; hazard ratio [HR] = 0.65 [95% confidence interval (CI), 0.54–0.77]; P < .001). Improvements in all secondary endpoints, including progression-free survival (PFS), response rates, and pain response, favored abiraterone acetate. This trial was followed by the COU-AA-302 phase III trial, in which 1,088 patients with mCRPC who had not received prior chemotherapy were randomly assigned to receive either abiraterone with prednisone or placebo with prednisone at established doses. The co-primary endpoints were radiographic PFS and OS. At a planned interim analysis, the radiographic PFS was improved with abiraterone (median, 16.5 vs 8.3 months; HR = 0.53 [95% CI, 0.45–0.62]; P < .001). At the time of the analysis, 333 deaths had occurred. The median OS for abiraterone had not been reached, compared with 27.2 months in the placebo arm (95% CI, 26 to NR [not reached]). There was a nonsignificant 25% reduction in the risk of death (HR = 0.75 [95% CI, 0.61–0.93]; P = .01). Abiraterone also delayed decline in performance status, time to initiation of cytotoxic chemotherapy, and time to initiation of opiate pain medications. The two trials resulted in the approval of abiraterone with prednisone for men with mCRPC.
Another novel androgen synthesis inhibitor, orteronel, selectively inhibits 17,20-lyase and suppresses androgen production in the adrenal glands and testicles in animal models. A phase I/II study established that orteronel is safe at doses ≥ 300 mg bid, with promising activity in men with CRPC. A unique property of orteronel is that at lower doses it can be administered safely without prednisone, likely due to its specificity for 17,20-lyase over CYP17-hydroxylase. However, ongoing phase III trials are evaluating orteronel 400 mg bid along with prednisone in both docetaxel-treated and docetaxel-naive men with mCRPC.
Androgen signaling inhibition has been achieved via direct AR blockade with drugs such as bicalutamide (Casodex), flutamide (Eulexin), and nilutamide (Nilandron), generally with a short duration of action. Clinical withdrawal responses upon cessation of anti-androgen therapy are seen in some patients and suggest a transition from antagonist to agonist behavior. Studies demonstrate that first-generation anti-androgens behave as agonists in the setting of AR overexpression. Bicalutamide impairs AR transcriptional activity by promoting recruitment of the AR transcriptional complex, including corepressors, to the promoter region of AR-dependent genes. When AR is overexpressed, bicalutamide recruits the AR transcriptional complex to the enhancer regions, along with coactivators, promoting transcription of AR-dependent genes. Understanding this adaptive resistance mechanism prompted development of novel AR antagonists.
Enzalutamide (Xtandi), a potent next-generation AR antagonist, binds to AR irreversibly and inhibits transcriptional activity without agonist properties in the setting of AR overexpression. Enzalutamide blocks nuclear translocation, DNA binding, and coactivator recruitment by the AR. Furthermore, enzalutamide demonstrates activity in prostate cancer cells expressing a mutant AR protein. In a phase I/II study, enzalutamide was administered to CRPC patients both with and without radiographic metastases, and in both chemotherapy-naive and pretreated populations. Of 140 men enrolled, PSA levels decreased by > 50% in approximately half. PSA responses were seen in all dose cohorts, and radiographic responses were observed in 22% of men with soft-tissue disease. The most common adverse effects were fatigue, nausea, diarrhea, constipation, and anorexia. Two patients had seizures confirmed by witnesses (at 360-mg and 600-mg doses) and one had a possible seizure (at a 480-mg dose). Thus, the maximum tolerated dose (MTD) was determined to be 240 mg/day. The phase III AFFIRM trial randomly assigned 1,199 men with mCRPC who had received prior docetaxel chemotherapy, in a 2:1 ratio, to treatment with either enzalutamide 160 mg/day or placebo. At a planned interim analysis after 520 deaths, the study was stopped, since the median OS with enzalutamide was 18.4 months (95% CI, 17.3 to NR), while with placebo it was 13.6 months (95% CI, 11.3 to 15.8) (HR = 0.63 [95% CI, 0.53–0.75]; P < .001). Enzalutamide demonstrated superiority in all secondary endpoints as well. Five seizures (0.6%) were observed, although some patients had predisposing features that could have lowered their seizure threshold. Enzalutamide was approved for use in men with mCRPC who have received prior docetaxel chemotherapy. Numerous ongoing and planned studies are evaluating enzalutamide in the prechemotherapy setting, as well as in combination with other agents.
Another AR antagonist in development, ARN-509, competitively inhibits AR signaling in the setting of AR overexpression, with potentially improved efficacy compared with enzalutamide in xenograft models. Plasma and brain levels of ARN-509 were lower than enzalutamide levels with equivalent dosing, yet tumor levels were equivalent, possibly because of lower plasma protein binding. A phase I study established a recommended dose of 240 mg/day; however, efficacy was seen across all dose levels. Common toxicities included fatigue, nausea, and pain. Phase II studies with ARN-509 are ongoing, with plans for a phase III randomized controlled trial in the near future.
The phosphatidylinositol 3-kinase (PI3K) family of enzymes is responsible for transducing a host of intracellular signals that facilitate cell survival and inhibit apoptosis. Activation of the PI3K/Akt signaling pathway leads to upregulation of mammalian target of rapamycin (mTOR) and nuclear factor kappa B (NF-ÎºB), thus inhibiting the p53 tumor suppressor and promoting cell growth and survival. Multiple germline mutations within the PI3K pathway have been implicated in the pathogenesis of malignancies. The tumor suppressor phosphatase and tensin homologue (PTEN) is a critical negative regulator of the PI3K pathway.[20,21] Loss of PTEN is the most prevalent genomic abnormality in both localized and metastatic prostate cancers, causing dysregulated PI3K signaling and contributing to the development of castration resistance.[22-24] This provides a rationale for evaluating agents targeting various components within the PI3K pathway.
Inhibitors of mTOR, including rapamycin analogues, have been studied in prostate cancer cell lines and xenografts, and demonstrate dose-dependent inhibition of mTOR and decreased phosphorylation of S6-kinase, the downstream target of mTOR. Inhibition of mTOR leads to modest reductions in prostate cancer growth and volume in mouse xenografts[25,26]; however, it failed to impact tumor proliferation or apoptosis in men with prostate cancer. A phase II clinical trial evaluating the mTOR complex 1 (mTORC1) inhibitor everolimus (Afinitor) with bicalutamide in men with CRPC demonstrated minimal activity; nonetheless, several trials evaluating everolimus in various combinations and settings are ongoing in prostate cancer. The lack of efficacy of mTOR inhibition may be due to interference with negative feedback, leading to activation of Akt and the mitogen-activated protein (MAP) kinase pathway.
PI3K Pathway Inhibitors in Development for Treatment of Prostate Cancer
Carver et al performed a series of experiments to better illustrate the relationship between the PI3K and AR signaling pathways in prostate cancer. BEZ235, a dual inhibitor of PI3K and mTORC1/2, was studied in PTEN-deficient prostate cancer xenografts. Treatment with BEZ235 decreased cell proliferation within the tumors but did not reduce tumor volume. Although AR levels were low in the PTEN-deficient mice, they could be partially restored upon treatment with BEZ235 or everolimus, as these interventions led to upregulation of human epidermal growth factor receptor 3 (HER3) and subsequent promotion of AR activity. Conversely, AR inhibition of PTEN-deficient xenografts with castration plus enzalutamide resulted in no changes in tumor volume, proliferation, or histology. Instead, Akt was upregulated, implying that AR signaling serves as negative feedback for the Akt pathway. Combining BEZ235 and enzalutamide in PTEN-deficient prostate cancer models led to profound tumor regression and apoptosis, indicating that PI3K (and/or mTORC1/2) and AR are critical cotargets in a PTEN-deficient prostate cancer model. Understanding this relationship provides a rational basis for clinical trial design that combines PI3K pathway inhibitors with potent AR antagonists in prostate cancer. Numerous PI3K pathway inhibitors that target PI3K, Akt, and mTORC1/2 are being developed. Selected trials utilizing PI3K pathway inhibitors in prostate cancer are summarized in Table 1.
Repair of ongoing damage to cellular DNA is critical for cell survival. Poly (adenosine diphosphate [ADP]-ribose) polymerases (PARPs) are enzymes that play a major role in repairing single-stranded DNA breaks via base excision. Single-stranded DNA breaks accumulate in the absence of PARP activity, and this can lead to double-stranded DNA breaks. The tumor suppressor proteins BRCA1 and BRCA2 are necessary components of the double-stranded DNA repair pathway. Germline mutations in BRCA1 or BRCA2 cripple the double-stranded DNA repair machinery, making affected individuals susceptible to breast, ovarian, and prostate cancers.[31,32] Cancers that carry BRCA1/2 mutations or other defects within the DNA damage repair pathways may be particularly sensitive to PARP inhibition. Although BRCA mutations are rare in prostate cancer, other abnormalities in DNA damage repair have been observed.
Gene fusions that involve the ETS family of transcription factor genes (ERG, ETV1, ETV4, ETV5) are present in 40% to 60% of prostate cancers; the most common of these is a fusion of ERG and the androgen-regulated transmembrane protease, serine 2 gene (TMPRSS2). The resultant androgen-stimulated overexpression of ERG has been associated with accelerated carcinogenesis in mouse prostates in the setting of PTEN loss; however, its role in disease progression remains unclear. DNA-dependent protein kinase is the large catalytic subunit of PI3/4-kinase and is necessary for repair of DNA strand breaks, specifically nonhomologous end-joining. Both PARP1 as well as DNA-dependent protein kinase interact with ERG and are necessary for ERG-mediated transcription in prostate cancer cells. Furthermore, PARP1 inhibition with olaparib prevents ERG-induced invasion and metastasis in prostate cancer cell lines positive for the ETS fusion gene.
In the phase I study of olaparib in patients with advanced solid tumor malignancies, a patient with mCRPC who was a BRCA2 mutation carrier experienced a prolonged clinical response with a greater than 50% reduction in PSA level and resolution of bone metastases. Veliparib, a PARP1/2 inhibitor, was tested along with temozolomide (Temodar) in a phase II study that involved 26 patients with mCRPC. Two patients exhibited significant declines in PSA levels; one patient had a 37% reduction in his PSA level, and the second patient had a 96% reduction in PSA level, as well as a 40% reduction in measurable tumor size. There are ongoing efforts to combine PARP inhibitors with radiation and abiraterone in prostate cancer (NCT01576172).
Oncologic therapies designed to kill cancer cells often trigger a stress response in the cancer cell, leading to activation of pro-survival pathways, and often conferring therapeutic resistance. Heat shock proteins (HSPs) serve as molecular chaperones that help cells cope with stress and that participate in cell signaling pathways and transcription regulation. HSP27 is a molecular chaperone, highly expressed in CRPC cells, that protects against apoptosis. Castration leads to increased expression of HSP27 in prostate cancer cells. HSP27 blocks castration-mediated apoptosis and fosters castration resistance. In prostate cancer, HSP27 may also displace HSP90 from the AR complex and facilitate shuttling of AR into the nucleus to act as a transcription factor. Inhibition of HSP27 with small interfering RNA (siRNA) or antisense oligonucleotides (ASOs) decreases prostate cancer cell proliferation, and increases caspase-3 activity and apoptosis, thereby increasing sensitivity to taxane chemotherapy.[39-41]
OGX-427 is a modified ASO that is complimentary to HSP27, blocks its expression, and enhances sensitivity to anticancer drugs. Treatment with OGX-427 induces apoptosis and promotes survival in several human cancer cell lines.[39-41] A phase I study assessed the dosing and safety of OGX-427, both alone and in combination with docetaxel, in patients with advanced solid tumors, including 27 with mCRPC. Single-agent treatment with OGX-427 was well tolerated at its maximum dose level (1,000 mg IV weekly on a 21-day schedule, after 3 loading doses), either alone or combined with docetaxel. Of the seven patients with CRPC and measurable disease who received OGX-427 plus docetaxel, two had confirmed partial responses and one had stable disease. A reduction in PSA level of ≥ 30% was observed in 3 of 16 patients who received OGX-427 alone and in 5 of 9 patients who received OGX-427 plus docetaxel. Additionally, correlative analysis of circulating tumor cell (CTC) counts demonstrated that of the 41 patients with pretreatment CTC levels > 5 per 7.5 mL, 37% observed a reduction in CTCs to ≤ 5 per 7.5 mL. A phase II trial randomly assigned 32 patients with mCRPC and no prior chemotherapy to treatment with OGX-427 and prednisone or prednisone alone. A reduction in PSA level of ≥ 50% was seen in 41% of patients in the OGX-427 arm and in 20% of patients in the prednisone-alone arm. In patients with measurable disease, a partial response was observed in 3 out of 8 patients in the OGX-427 arm but in none of the 9 patients in the prednisone arm. Reductions in CTC levels and in PFS at 12 weeks both favored OGX-427. The study is now fully accrued, and mature data are pending.
Secretory clusterin is a cytoprotective small HSP chaperone that inhibits protein aggregation in response to cellular stress. Clusterin inhibits BAX, blocking stress-induced activation of the Bcl-2–mediated apoptotic pathway, and it prevents release of cytochrome C from the mitochondria. Overexpression of clusterin also leads to increased phosphorylation of Akt, promoting nuclear transactivation of NF-ÎºB and cell survival. Increased expression of clusterin in cancer cells is associated with resistance to cytotoxic drug–induced cell death, including androgen deprivation–induced apoptosis in prostate cancer cells. Targeting secretory clusterin is not possible with traditional agents and has only been feasible with the use of siRNA/ASO-mediated inhibition.[44,45]
Custirsen (OGX-011) is a potent second-generation ASO inhibitor of the translation initiation site of human exon II clusterin, which suppresses expression of clusterin in vitro and in vivo. Treatment with custirsen significantly reduces secretory clusterin levels, enhancing the efficacy of chemotherapy, radiation, and ADT, and increasing apoptosis in several xenograft models, including models of prostate, breast, lung, kidney, and bladder cancers.[46,47] A phase I study investigated custirsen in patients with localized prostate cancer, using a presurgical escalating dose level trial design to allow for evaluation of tumor tissue clusterin expression after treatment with custirsen. Patients received a single 6.3-mg dose of buserelin acetate (2-month depot formulation), as well as flutamide, 250 mg tid for 28 days. Custirsen was administered as an IV infusion on days 1, 3, and 5, and then weekly (on days 8, 15, 22, and 29). Patients underwent prostatectomy within 1 week of their last dose of custirsen. Twenty-five patients were enrolled in custirsen 40-, 80-, 160-, 320-,
480-, and 640-mg dose cohorts. No dose-limiting toxicities were observed. The most common side effects included fever, fatigue, rigors, and myelosuppression. Treatment with custirsen was associated with a statistically significant dose-dependent decrease in clusterin messenger RNA (mRNA) and protein expression. Decreased clusterin mRNA and protein expression in the tissue correlated with increased tumor apoptosis. A second phase I study evaluating custirsen administered on days 1, 3, and 5, and then weekly in combination with docetaxel demonstrated that custirsen could be safely administered at a full (640-mg) dose along with docetaxel without dose-limiting toxicities. An 82-person randomized phase II trial compared docetaxel and prednisone with custirsen (arm A) vs docetaxel and prednisone without custirsen (arm B) in men with mCRPC who had not received prior chemotherapy. The primary endpoint was the proportion of patients with a ≥ 50% reduction in PSA level; the results showed no appreciable difference between arms A and B (58% vs 54%, respectively). The median PFS and OS were 7.3 months (95% CI, 5.3–8.8) and 23.8 months (95% CI, 6.2 to NR), respectively, in arm A; and 6.1 months (95% CI, 3.7–8.6) and 16.9 months (95% CI, 12.8–25.8), respectively, in arm B. Although there was no significant improvement in PFS, a multivariate analysis revealed a statistically significant improvement in OS. Based on the survival benefit seen in phase II, the SYNERGY phase III trial has completed accrual, randomly assigning men with mCRPC to treatment with docetaxel and prednisone either with or without custirsen, with OS as the primary endpoint (NCT01188187). Additionally, the AFFINITY randomized phase III trial is currently evaluating cabazitaxel (Jevtana) and prednisone with or without custirsen as second-line chemotherapy in men with mCRPC (NCT01578655).
Tissue invasion and metastasis are inherent characteristics of cancers. MET is a proto-oncogene that encodes a receptor tyrosine kinase responsible for promoting cell motility and growth.[51,52] MET activation by its ligand, hepatocyte growth factor (HGF), triggers signaling via the Ras-Raf-ERK/mitogen-activated protein kinase (MAPK) pathway, as well as the PI3K/Akt pathway, resulting in transcription of growth-, proliferation-, and survival-promoting genes. Studies in epithelial cell lines have demonstrated that activation of MET leads to cell dissociation and subsequent invasion of a collagen matrix, which correlates with the invasive and metastatic potential of the cell.[53,54]
Cabozantinib (XL184) is a potent inhibitor of MET and vascular endothelial growth factor receptor 2 (VEGFR2), and has demonstrated activity in cells that overexpress wild-type MET, as well as in cells with activating mutations. Treatment with cabozantinib leads to decreased tumor and endothelial cell proliferation, as well as increased apoptosis, in xenograft models. Moreover, cabozantinib did not increase metastatic tumor burden, a phenomenon that has been seen with other VEGF-signaling inhibitors. Cabozantinib demonstrated an acceptable safety profile in a phase I study in patients with advanced solid malignancies. A phase II trial evaluated cabozantinib in men with mCRPC. Investigators used a randomized discontinuation adaptive design in which patients received cabozantinib 100 mg daily for 12 weeks, at which time those with stable disease were randomly assigned to either continued cabozantinib or placebo. Randomization was suspended after enrollment of 122 patients, due to high response rates and symptomatic improvement during the lead-in phase of the trial; a total of 171 patients with prostate cancer were enrolled. Of the 154 patients who had disease evaluable by RECIST criteria, 9 patients had confirmed partial responses, 127 had stable disease, and 18 had disease progression. After observation of significant bone scan changes, a post-hoc analysis was performed. Of the 116 patients with bone metastases and at least one follow-up bone scan, 68% had improvement and 12% had complete resolution of all skeletal metastases on bone scan. Improvement in markers of bone turnover, as well as pain improvement, was seen in responding patients; however, PSA levels did not correlate with bone or soft-tissue responses. Given the impressive early activity, the COMET-1 phase III double-blind placebo-controlled trial is currently evaluating OS for cabozantinib vs prednisone in men with mCRPC whose disease had progressed on prior docetaxel and either abiraterone or enzalutamide (NCT01605227).
Neovascularization, the development and growth of new blood vessels, is critical for malignant cell proliferation, invasion, and metastasis. Activation of endothelial cells via release of angiogenic peptides, most notably VEGF, leads to new vessel formation. The VEGFR complex includes several ligands (VEGF-A, -B, -C, -D, and -E, and placental growth factor) and their associated receptors (VEGFR1/FLT1, VEGFR2/KDR, VEGFR3/FLT4, and neuropilin-1 and -2). VEGF-A expression by cancer cells is critical for angiogenesis and tumor growth. VEGFR activation leads to endothelial cell proliferation and migration, changes in the extracellular matrix, increased vascular dilation and permeability, and inhibition of endothelial cell apoptosis (which promotes survival of newly formed blood vessels). In prostate cancer, ADT leads to decreased VEGF mRNA and protein expression, as well as to a corresponding reduction in new blood vessel formation.
Inhibition of angiogenesis has played a crucial role in the treatment of several cancers. Multiple antiangiogenic drugs have been developed and are in use in different tumor types, including monoclonal antibodies and tyrosine kinase inhibitors. Bevacizumab (Avastin), a humanized monoclonal antibody targeting VEGF, was first approved in 2004 for use along with chemotherapy in metastatic colon cancer; it is also currently approved for use in metastatic non–small-cell lung cancer, ovarian cancer, glioblastoma, and renal cell carcinoma.
Randomized Phase III Prostate Cancer Trials With Antiangiogenic Agents
Antiangiogenic properties of the chemotherapeutic drug docetaxel induce VEGF overexpression in docetaxel-treated cancer cells; however, the addition of bevacizumab overcomes this resistance mechanism. A phase II trial evaluating bevacizumab in men with mCRPC and progression after docetaxel chemotherapy suggested activity based on PSA responses. Unfortunately, the phase III trial of docetaxel and prednisone with bevacizumab or placebo in men with mCRPC showed no difference in OS between the bevacizumab and placebo arms (median, 22.6 vs 21.5 months; HR = 0.91 [95% CI, 0.78–1.05]; P = .181). Trials evaluating several other antiangiogenic agents, including sunitinib (Sutent), aflibercept (Zaltrap), and lenalidomide (Revlimid), in mCRPC have also failed to demonstrate significant clinical benefit (Table 2).[65-67]
Despite the negative results from previous trials with antiangiogenic agents, there are still other promising antiangiogenic agents in development for the treatment of mCRPC. Tasquinimod is a second-generation, orally active quinolone-3-carboxamide analogue that demonstrates antiangiogenic and antineoplastic properties. Potential mechanisms of action include binding to S100A9, which can regulate cell-cycle progression and differentiation, as well as upregulate expression of thrombospondin-1, an inhibitor of angiogenesis. In both castration-sensitive and castration-resistant xenograft prostate cancer models, treatment with tasquinimod reduced tumor volume and new blood vessel formation and enhanced antitumor activity when combined with ADT and docetaxel. The phase I trial in men with CRPC demonstrated that tasquinimod (MTD, 0.5 mg daily) was safe and well tolerated, with anemia, nausea, fatigue, myalgia, and pain among the most common toxicities. A randomized, double-blind, placebo-controlled phase II trial was performed in men with minimally symptomatic CRPC. Two hundred one men were randomly assigned in a 2:1 fashion to receive either tasquinimod 0.25 mg/day escalating to 1.0 mg/day over 4 weeks (n = 134) or placebo (n = 67). There was a statistically significant difference in 6-month PFS (the primary endpoint) between tasquinimod (69%) and placebo (37%). In addition, a significant improvement in median PFS was seen in the tasquinimod arm (7.6 months vs 3.3 months; P = .0042). A phase III trial comparing tasquinimod vs placebo in chemotherapy-naive men with minimally symptomatic mCRPC has completed accrual; results are pending.
Treatment paradigms for men with mCRPC have changed dramatically in the last 3 years due to regulatory approval of agents like abiraterone and enzalutamide, as well as other agents not discussed in this review, such as sipuleucel-T (Provenge), cabazitaxel (Jevtana), denosumab (Xgeva), and radium-223 (Xofigo). Identifying predictive biomarkers and selecting sensitive patient populations present unique challenges for future drug development. Ascertainment of resistance mechanisms will lead to informed therapeutic decision making. Some of these resistance mechanisms may have been addressed by the molecular pathways, targets, and therapeutic agents discussed in this review, although many distinct mechanisms remain undiscovered, leaving room for progress. Individualizing treatment with knowledge of these biologic mechanisms will lead to more effective therapeutic sequencing and rational drug combinations. These efforts necessitate ongoing translational research, including tissue acquisition from tumor metastases and molecular characterization of circulating tumor cells.
Despite refining the use of novel AR signaling inhibitors, therapeutic resistance naturally occurs, and it remains unlikely that cures will be seen with current treatment strategies. It is also possible that the prostate cancer cells that emerge resistant to these potent new hormonal agents will be dependent upon alternative signaling pathways, and could potentially exhibit extraordinarily aggressive behavior. For this reason, efforts must continue not only to bolster the discovery process for new biologic targets through personalized cancer medicine initiatives, but also to optimize development of next-generation targeted therapies.
Financial Disclosure: Dr. Yu has received honoraria for consulting services for Amgen, Astellas, Dendreon, Janssen Pharmaceuticals, and Medivation; he has received research funding from Dendreon, Janssen, and OncoGeneX. Dr. Derleth has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Howlader N, Noone AM, Krapcho M, et al. SEER cancer statistics review, 1975-2009 (vintage 2009 populations). 2012; based on November 2011 SEER data submission, posted to the SEER website, 2012.
2. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138-48.
3. Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293-7.
4. Hu R, Lu C, Mostaghel EA, et al. Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res. 2012;72:3457-62.
5. Mostaghel EA, Page ST, Lin DW, et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007;67:5033-41.
6. Sun S, Sprenger CC, Vessella RL, et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest. 2010;120:2715-30.
7. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787-90.
8. Haidar S, Ehmer PB, Barassin S, et al. Effects of novel 17alpha-hydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. J Steroid Biochem Mol Biol. 2003;84:555-62.
9. Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol. 2010;28:1481-8.
10. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.
11. Yamaoka M, Hara T, Hitaka T, et al. Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. J Steroid Biochem Mol Biol. 2012;129:115-28.
12. Dreicer R, Agus DB, MacVicar GR, et al. Safety, pharmacokinetics, and efficacy of TAK-700 in metastatic castration-resistant prostate cancer: a phase I/II, open-label study. J Clin Oncol. 2010;28:15s.
13. George DJ, Corn PG, Michaelson MD, et al. Safety and activity of the investigational agent orteronel (ortl) without prednisone in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) and rising prostate-specific antigen (PSA): updated results of a phase II study. J Clin Oncol. 2012;30(suppl):Abstr 4549.
14. Scher HI, Kelly WK. Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer. J Clin Oncol. 1993;11:1566-72.
15. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33-9.
16. Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010;375:1437-46.
17. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-97.
18. Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012;72:1494-503.
19. Rathkopf DE, Morris MJ, Danila DC, et al. A phase I study of the androgen signaling inhibitor ARN-509 in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2012;30(suppl):abstr 4548.
20. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8:627-44.
21. Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA. 1999;96:4240-5.
22. El Sheikh SS, Romanska HM, Abel P, et al. Predictive value of PTEN and AR coexpression of sustained responsiveness to hormonal therapy in prostate cancer-a pilot study. Neoplasia. 2008;10:949-53.
23. Reid AH, Attard G, Ambroisine L, et al. Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer. Br J Cancer. 2010;102:678-84.
24. Jiao J, Wang S, Qiao R, et al. Murine cell lines derived from PTEN null prostate cancer show the critical role of PTEN in hormone refractory prostate cancer development. Cancer Res. 2007;67:6083-91.
25. Wu L, Birle DC, Tannock IF. Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells and xenografts. Cancer Res. 2005;65:2825-31.
26. Zhang W, Zhu J, Efferson CL, et al. Inhibition of tumor growth progression by antiandrogens and mTOR inhibitor in a PTEN-deficient mouse model of prostate cancer. Cancer Res. 2009;69:7466-72.
27. Armstrong AJ, Netto GJ, Rudek MA, et al. A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer. Clin Cancer Res. 2010;16:3057-66.
28. Nakabayashi M, Werner L, Courtney KD, et al. Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer. BJU Int. 2012;110:1729-35.
29. Carracedo A, Ma L, Teruya-Feldstein J, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118:3065-74.
30. Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell. 2011;19:575-86.
31. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst. 1999;91:1310-6.
32. Ford D, Easton DF, Bishop DT, et al. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994;343:692-5.
33. Schaefer G, Mosquera JM, Ramoner R, et al. Distinct ERG rearrangement prevalence in prostate cancer: higher frequency in young age and in low PSA prostate cancer. Prostate Cancer Prostatic Dis. 2013;16:132-8.
34. Carver BS, Tran J, Gopalan A, et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet. 2009;41:619-24.
35. Brenner JC, Ateeq B, Li Y, et al. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell. 2011;19:664-78.
36. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123-34.
37. Hussain M, Carducci M, Slovin S, et al. Pilot study of veliparib (ABT-888) with temozolomide in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2012;30(suppl 5):abstr 224.
38. Zoubeidi A, Zardan A, Beraldi E, et al. Cooperative interactions between androgen receptor (AR) and heat-shock protein 27 facilitate AR transcriptional activity. Cancer Res. 2007;67:10455-65.
39. Andrieu C, Taieb D, Baylot V, et al. Heat shock protein 27 confers resistance to androgen ablation and chemotherapy in prostate cancer cells through eIF4E. Oncogene. 2010;29:1883-96.
40. Rocchi P, Jugpal P, So A, et al. Small interference RNA targeting heat-shock protein 27 inhibits the growth of prostatic cell lines and induces apoptosis via caspase-3 activation in vitro. BJU Int. 2006;98:1082-9.
41. Rocchi P, So A, Kojima S, et al. Heat shock protein 27 increases after androgen ablation and plays a cytoprotective role in hormone-refractory prostate cancer. Cancer Res. 2004;64:6595-602.
42. Hotte SJ, Yu EY, Hirte HW, et al. Phase I trial of OGX-427, a 2'-methoxyethyl antisense oligonucleotide (ASO), against heat shock protein 27 (Hsp27): final results. J Clin Oncol. 2010;28:15s.
43. Chi KN, Hotte SJ, Ellard S, et al. A randomized phase II study of OGX-427 plus prednisone (P) versus P alone in patients (pts) with metastatic castration resistant prostate cancer (CRPC). J Clin Oncol. 2012;30(suppl):abstr 4514.
44. Zoubeidi A, Chi K, Gleave M. Targeting the cytoprotective chaperone, clusterin, for treatment of advanced cancer. Clin Cancer Res. 2010;16:1088-93.
45. Zoubeidi A, Ettinger S, Beraldi E, et al. Clusterin facilitates COMMD1 and I-kappaB degradation to enhance NF-kappaB activity in prostate cancer cells. Mol Cancer Res. 2010;8:119-30.
46. Gleave M, Miyake H. Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer. World J Urol. 2005;23:38-46.
47. Sowery RD, Hadaschik BA, So AI, et al. Clusterin knockdown using the antisense oligonucleotide OGX-011 re-sensitizes docetaxel-refractory prostate cancer PC-3 cells to chemotherapy. BJU Int. 2008;102:389-97.
48. Chi KN, Eisenhauer E, Fazli L, et al. A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2'-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. J Natl Cancer Inst. 2005;97:1287-96.
49. Chi KN, Siu LL, Hirte H, et al. A phase I study of OGX-011, a 2'-methoxyethyl phosphorothioate antisense to clusterin, in combination with docetaxel in patients with advanced cancer. Clin Cancer Res. 2008;14:833-9.
50. Chi KN, Hotte SJ, Yu EY, et al. Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28:4247-54.
51. Cooper CS, Park M, Blair DG, et al. Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature. 1984;311:29-33.
52. Nakamura T, Nishizawa T, Hagiya M, et al. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989;342:440-3.
53. Weidner KM, Behrens J, Vandekerckhove J, Birchmeier W. Scatter factor: molecular characteristics and effect on the invasiveness of epithelial cells. J Cell Biol. 1990;111:2097-108.
54. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4:915-25.
55. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298-308.
56. Kurzrock R, Sherman SI, Ball DW, et al. Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011;29:2660-6.
57. Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013;31:412-9.
58. Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell. 1994;79:185-8.
59. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997;18:4-25.
60. Ferrara N, Alitalo K. Clinical applications of angiogenic growth factors and their inhibitors. Nat Med. 1999;5:1359-64.
61. Stewart RJ, Panigrahy D, Flynn E, Folkman J. Vascular endothelial growth factor expression and tumor angiogenesis are regulated by androgens in hormone responsive human prostate carcinoma: evidence for androgen dependent destabilization of vascular endothelial growth factor transcripts. J Urol. 2001;165:688-93.
62. Sweeney CJ, Miller KD, Sissons SE, et al. The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors. Cancer Res. 2001;61:3369-72.
63. Di Lorenzo G, Figg WD, Fossa SD, et al. Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur Urol. 2008;54:1089-94.
64. Kelly WK, Halabi S, Carducci M, et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol. 2012;30:1534-40.
65. Michaelson MD, Oudard S, Ou Y, et al. Randomized, placebo-controlled, phase III trial of sunitinib in combination with prednisone (SU+P) versus prednisone (P) alone in men with progressive metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2011;29(suppl):abstr 4515.
66. Tannock I, Fizazi K, Ivanov S, et al. Aflibercept versus placebo in combination with docetaxel/prednisone for first-line treatment of men with metastatic castration-resistant prostate cancer (mCRPC): Results from the multinational phase III trial (VENICE). J Clin Oncol. 2013;31(suppl 6):abstr 13.
67. Petrylak DP, Fizazi K, Sternberg CN, et al. A phase 3 study to evaluate the efficacy and safety of docetaxel and prednisone with or without lenalidomide in patients with castrate-resistant prostate cancer (CRPC): The MAINSAIL trial. 2012 ESMO Congress. 2012;Abstr LBA24.
68. Dalrymple SL, Becker RE, Isaacs JT. The quinoline-3-carboxamide anti-angiogenic agent, tasquinimod, enhances the anti-prostate cancer efficacy of androgen ablation and taxotere without effecting serum PSA directly in human xenografts. Prostate. 2007;67:790-7.
69. Bratt O, Haggman M, Ahlgren G, et al. Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer. Br J Cancer. 2009;101:1233-40.
70. Pili R, Haggman M, Stadler WM, et al. Phase II randomized, double-blind, placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer. J Clin Oncol. 2011;29:4022-8.
71. Bendell JC, Rodon J, Burris HA, et al. Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2012;30:282-90.
72. Yap TA, Yan L, Patnaik A, et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol. 2011;29:4688-95.