Recent advances in research technologies have allowed improved molecular characterization of castration-resistant prostate cancer (CRPC). These efforts hold promise for development of therapies that target alterations unique to an individual patient’s prostate cancer. Targets include androgens and the androgen receptor pathway, pathways associated with hormone-resistant disease, and the immune system. In aggregate, this will allow physicians to choose treatments based on a particular tumor profile. As these approaches are developed, CRPC treatment is becoming an example of truly personalized medicine.
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Next-generation sequencing has allowed improved characterization of castration-resistant prostate cancer.
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Novel targeted therapies can focus on insights into the biology of androgen receptor and the androgen synthesis pathways.
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Novel therapies target genomic susceptibilities of distinct subgroups.
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Tailored immunotherapy is another personalized approach to therapy.
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New methods to implement these technologies in prospective clinical settings are underway.
Introduction
Across cancer types, recent genomic studies have revealed genetic polymorphisms and mutations that may serve as therapeutic targets. Based on these findings and the increasing ability to identify biologically and clinically relevant genetic alterations, the era of personalized cancer treatment is achievable. This potential shift in clinical practice represents a transformation in oncology that may dramatically improve outcomes for patients who have cancer. Personalized approaches to cancer care have recently demonstrated clinically significant benefit, including targeting the activation of the gene BRAF in metastatic melanoma and the EML4-ALK gene fusion in metastatic non–small-cell lung cancer. By defining subpopulations of patients based on specific genetic, “druggable” alterations (ie, genetic alterations for which therapies exist), these examples demonstrate not only the feasibility but often the superiority of a personalized approach to cancer care when compared with nonpersonalized standard therapies.
Prostate cancer (CaP) is the most common solid tumor in men in the United States. CaP is considered a hormone-dependent tumor in which malignant cells express the androgen receptor (AR) and require its activation for survival. Castration-resistant prostate cancer (CRPC) refers to the clinical state in which resistance to androgen deprivation therapy (ADT) has emerged and disease progression results despite castrate levels of testosterone (typically defined as ≤50 ng/dL). Castration resistance is associated with a poor prognosis and metastatic CRPC is generally considered lethal. Traditional therapeutic approaches to CRPC have included primarily cytotoxic chemotherapy, specifically docetaxel plus prednisone, yielding a median overall survival of approximately 18 months in the metastatic setting.
However, an improved understanding of the biologic mechanisms leading to ADT resistance and CRPC emergence has resulted in multiple novel therapeutic approaches targeting specific vulnerabilities of the tumor cell. These include innovative androgen-based therapies, building on the full genomic characterization of CRPC, and immunotherapy-based approaches, targeting CRPC-related antigens ( Table 1 ). Taken together, these approaches form the basis for targeted therapies for CRPC and will be described sequentially in detail.
| Target | Agent | Stage of Therapy |
|---|---|---|
| Androgen production | Abiraterone | FDA approved |
| — | Tak-700 | Early-phase clinical trials |
| — | Tok-001 | Early-phase clinical trials |
| AR binding | MDV-3100 | Phase III trials |
| — | ARN-509 | Early-phase clinical trials |
| — | Tok-001 | Early-phase clinical trials |
| ETS-positive | PARP1 inhibitors | Early-phase clinical trials |
| SPINK1 overexpressed | Cetuximab | Early-phase clinical trials |
| — | Erlotinib | Early-phase clinical trials |
| PI3K pathway a | PI3K inhibitors | Early-phase clinical trials |
| — | AKT inhibitors | Early-phase clinical trials |
| — | mTOR inhibitors | Early-phase clinical trials |
| MAPK pathway | RAF inhibitors | Early-phase clinical trials |
| — | MEK inhibitors | Early-phase clinical trials |
| Immunotherapy | Sipuleucel-T | FDA approved |
| — | Ipilimumab | Phase III trials |
Personalized medicine in oncology
To realize the potential of personalized medicine in CRPC, an appreciation of this approach in other cancers is worthwhile. One prominent recent example involves a new treatment paradigm for metastatic melanoma. Before there was a clear understanding of the potential drivers of this disease, standard first-line therapy included nonspecific cytotoxic chemotherapy or immunotherapy and no systemic therapy-demonstrated improved overall survival.
However, once activating mutations in the BRAF gene were discovered in approximately 50% of patients with advanced melanoma, targeted therapies directed specifically at that alteration were developed and studied specifically in those patients who harbored the recurrent activating mutation in BRAF. These efforts culminated in the development of vemurafenib (Zelboraf), an agent directed at a specific activating mutation in BRAF that demonstrated improved overall survival in advanced melanoma. Vemurafenib is now Food and Drug Administration (FDA) approved, along with a diagnostic test that identifies the activating BRAF alteration that warrants use of this agent. Patients with newly diagnosed metastatic melanoma are routinely tested for this mutation to choose the appropriate first-line therapy.
This approach can be summarized as follows: (1) define a clinical cohort of patients whose tumors harbor specific molecular alterations, (2) utilize agents that selectively target those alterations, and (3) match patients to drugs. This tailored therapy method serves as a model for similar efforts in CRPC, using the numerous pathways and alterations involved in this disease.
Personalized medicine in oncology
To realize the potential of personalized medicine in CRPC, an appreciation of this approach in other cancers is worthwhile. One prominent recent example involves a new treatment paradigm for metastatic melanoma. Before there was a clear understanding of the potential drivers of this disease, standard first-line therapy included nonspecific cytotoxic chemotherapy or immunotherapy and no systemic therapy-demonstrated improved overall survival.
However, once activating mutations in the BRAF gene were discovered in approximately 50% of patients with advanced melanoma, targeted therapies directed specifically at that alteration were developed and studied specifically in those patients who harbored the recurrent activating mutation in BRAF. These efforts culminated in the development of vemurafenib (Zelboraf), an agent directed at a specific activating mutation in BRAF that demonstrated improved overall survival in advanced melanoma. Vemurafenib is now Food and Drug Administration (FDA) approved, along with a diagnostic test that identifies the activating BRAF alteration that warrants use of this agent. Patients with newly diagnosed metastatic melanoma are routinely tested for this mutation to choose the appropriate first-line therapy.
This approach can be summarized as follows: (1) define a clinical cohort of patients whose tumors harbor specific molecular alterations, (2) utilize agents that selectively target those alterations, and (3) match patients to drugs. This tailored therapy method serves as a model for similar efforts in CRPC, using the numerous pathways and alterations involved in this disease.
Targeting the androgen pathway
In CRPC, despite depleted circulating androgen, AR activity is restored by numerous mechanisms. Clinically, this phenomenon is manifested by rising prostate-specific antigen (PSA) levels and, recently, the underlying biologic processes have been characterized. These mechanisms of increased AR activity include (1) AR amplification or overexpression, (2) activating AR mutations, (3) alternative sources of androgen production, (4) AR coactivator overexpression, and (5) indirect AR activation. Globally, these mechanisms involve either an increase in AR ligand or AR activation. Multiple novel approaches are in development to specifically target these events.
AR Ligand Reduction
Traditional approaches to androgen depletion in the treatment of prostate cancer include GnRH agonists, which desensitize gonadotropin release and suppress testicular androgen production. In addition, the antifungal agent ketoconazole has long been used to suppress the contribution of androgen from the adrenal gland. Neither approach is particularly specific to AR ligand reduction, nor are they associated with common side effects such as decreased bone density or clinical adrenal insufficiency.
With the discovery that nontesticular sources of androgen maintain some androgen production and promote prostate cancer progression, multiple targeted approaches have emerged to translate this resistance pathway into a susceptibility. The most developed therapy targeting residual androgen deprivation is abiraterone acetate (Zytiga), a highly selective irreversible inhibitor of CYP17A1 (17α–hydroxylase/C17,20-lyase), an enzyme involved in androgen synthesis. Ketoconazole more crudely inhibits this enzyme along with additional enzymes in adrenal biosynthesis pathways.
In a phase II study of CRPC patients who had already progressed despite docetaxel, administration of abiraterone acetate resulted in a PSA decline of greater than or equal to 30% in 32 of 47 patients and was quite well tolerated. A subsequent phase III study involving this patient population demonstrated a significant improvement in overall survival in the abiraterone acetate arm, with a 14.8 month (vs 10.9 months) overall survival and a hazard ratio of 0.646. Additional therapies targeting CYP17 that are currently in development and clinical study include Tak-700 (Millennium Pharmaceuticals, Cambridge, MA, USA and Takeda, Osaka, Japan) and Tok-001 (Tokai Pharmaceuticals, Cambridge, MA, USA), which also acts as an AR antagonist.
AR Deactivation
Direct inhibition of AR remains a frequently used therapeutic maneuver and a logical treatment strategy. However, first-generation AR antagonists, such as bicalutamide, or mixed agonists-antagonists, such as flutamide, have had limited clinical benefit. One potential mechanism of resistance to these therapies is that alternative splicing of AR leads to alteration or loss of the ligand-binding domain to which traditional AR-targeted therapies bind. Another resistance mechanism invokes AR copy number amplification, which may affect AR coactivators and result in the medications functioning predominantly as agonists instead of than antagonists. In this setting, antiandrogens can promote instead of than inhibit tumor growth.
As a result, two new AR antagonists have been developed to potentially circumvent these resistance mechanisms. MDV3100 (Medivation, San Francisco, CA, USA) is a small-molecule antagonist of AR that binds to AR with higher affinity than traditional antiandrogens. In addition, it inhibits AR translocation to the nucleus and blocks AR–DNA binding. A phase I-II study of 42 patients with CRPC and progressive disease demonstrated a 50% or greater reduction in PSA in 56% of patients. Based on these findings, multiple phase III trials have been initiated in the before and after chemotherapy settings, with preliminary results expected in the next 1 to 2 years.
ARN-509 (Aragon, San Diego, CA, USA) is a competitive AR inhibitor that is antagonistic to AR overexpression and, unlike traditional AR antagonists, lacks agonist activity in preclinical CRPC models. It functions by binding to AR, inhibiting cell growth and androgen-mediated transcription in CaP that overexpresses AR, thereby suppressing tumor growth. Phase II studies of this agent are ongoing. Finally, Tok-001 combines CYP17 inhibition with AR targeting and is in clinical trials.
Current AR Precision Therapy Limitations
Though a better understanding of AR biology has led to multiple therapies targeting susceptibilities in this pathway, there is not yet a method to identify in advance which CRPC patients may benefit most from targeting this pathway or which specific targets within the pathway deserve the most attention in an individual patient. Although there is no clinical test for quantifying AR copy number amplification to predict which patients may benefit the most from AR antagonists, predictive assays such as this may prove beneficial in the future. In addition, incorporation of serial biopsies of patient lesions after initial resistance to ADT therapy may help determine which resistance mechanism developed in that patient’s tumor and what AR-targeted agent, if any, might be clinically useful. Recent genetic sequencing of CRPC tumor samples suggest that mutations in AR and other key genes in its pathway occur as the disease progresses and may offer clues about how to attack ADT-resistant disease.
In sum, discoveries in AR biology have led to multiple therapies strategically designed to attack CRPC-related susceptibilities. As a class of agents, these newer androgen-related therapies are more specific than their predecessors in targeting AR and the androgen pathway. Although they demonstrate a great step in the direction of truly personalized CRPC therapy, they are still clinically used without specific knowledge of the individual patient’s tumor profile. However, when combined with some additional findings (see later discussion), these agents will likely form the foundation of a personalized approach to CRPC management. Furthermore, as data are accumulated on inherited variation in androgen synthesis pathways, such as genetic polymorphisms in CYP17 and their impact on survival, it is conceivable that selection of these agents will be based on a patient’s predicted ability to respond to such agents. Studies addressing variations in the androgen pathway are ongoing.
Related posts:
Targeting the Androgen Receptor
Palliative Care in Castrate-Resistant Prostate Cancer
Quality of Life with Advanced Metastatic Prostate Cancer
The Experience with Cytotoxic Chemotherapy in Metastatic Castration-Resistant Prostate Cancer
Management of Docetaxel Failures in Metastatic Castrate-Resistant Prostate Cancer
Targeting Angiogenesis as a Promising Modality for the Treatment of Prostate Cancer
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