Targeted Therapy in the Treatment of Castration-Resistant Prostate Cancer
Targeted Therapy in the Treatment of Castration-Resistant Prostate Cancer
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.
Next-Generation Androgen Synthesis Inhibitors and AR Signaling Inhibitors
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 PI3K Signaling Pathway
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-κB), 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.
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.