Hormone Therapy For Prostate Cancer Research Articles

Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer.

Androgen deprivation therapy (ADT) is initially effective in treating metastatic prostate cancer, and secondary hormonal therapies are being tested to suppress androgen receptor (AR) reactivation in castration-resistant prostate cancer (CRPC). Despite variable responses to AR pathway inhibitors in CRPC, there are no reliable biomarkers to guide their application. Here, we used microfluidic capture of circulating tumor cells (CTC) to measure AR signaling readouts before and after therapeutic interventions. Single-cell immunofluorescence analysis revealed predominantly "AR-on" CTC signatures in untreated patients, compared with heterogeneous ("AR-on, AR-off, and AR-mixed") CTC populations in patients with CRPC. Initiation of first-line ADT induced a profound switch from "AR-on" to "AR-off" CTCs, whereas secondary hormonal therapy in CRPC resulted in variable responses. Presence of "AR-mixed" CTCs and increasing "AR-on" cells despite treatment with abiraterone acetate were associated with an adverse treatment outcome. Measuring treatment-induced signaling responses within CTCs may help guide therapy in prostate cancer. Acquired resistance to first-line hormonal therapy in prostate cancer is heterogeneous in the extent of AR pathway reactivation. Measurement of pre- and posttreatment AR signaling within CTCs may help target such treatments to patients most likely to respond to second-line therapies.

Landmarks in hormonal therapy for prostate cancer

• It is >70 years since the responsiveness of symptomatic metastatic prostate cancer to androgen deprivation was first demonstrated. • Since those pivotal studies, progress in hormonal therapy of prostate cancer has been marked by several important developments and the availability of various androgen-suppressing agents. • Treatment guidelines have continued to evolve with clinical and therapeutic progress, but androgen-deprivation therapy (ADT) remains the standard of care for non-localised prostate cancer. • Because of the long-term experience (>20 years) and wealth of evidence from the large number of clinical trials, the luteinizing hormone-releasing hormone (LHRH) agonists are currently the main forms of ADT. • Treatment strategies should be adapted to the individual patient in terms of timing, duration and choice of agent. • Prostate cancer remains the most common type of cancer in men and the development of castration-resistant disease seems inevitable, which together drive the clear and continuing need for new, effective agents for ADT to be used alongside the LHRH agonists.

Role of hormonal therapy for prostate cancer: perspective from Japanese experiences.

Hormonal therapy has been playing an important role in the treatment of prostate cancer. However, it has recently been the subject of criticism that it shows minimal effectiveness, it may reduce patients’ quality of life, and induce adverse effects. On the other hand, next-generation hormonal drugs have provided new strategies for hormonal therapy to overcome advanced prostate cancer. Therefore, it is necessary to accumulate further clinical evidence concerning the efficacy and adverse effects of hormonal therapy. And, what is important for the treatment of prostate cancer is how we use hormonal therapy most effectively. This article presents a review of the possible roles of hormonal therapy for prostate cancer based upon experience in Japan.

Posttreatment Prostate Specific Antigen Nadir Predicts Prostate Cancer Specific and All Cause Mortality

We investigated whether the prostate specific antigen nadir predicts prostate cancer specific and all cause mortality in men treated in a randomized trial of radiation with or without 6 months of androgen deprivation therapy. The study included 204 men with cT1b-T2bN0M0 prostate adenocarcinoma and at least 1 unfavorable factor, including prostate specific antigen less than 10 to 40 ng/ml, Gleason 7 or greater, or T3 on magnetic resonance imaging. We performed Fine and Gray regression, and Cox multivariable analysis to determine whether an increasing prostate specific antigen nadir was associated with prostate cancer specific and all cause mortality, adjusting for treatment, age, Adult Comorbidity Evaluation 27 score and cancer prognostic factors. At a 6.9-year median followup median prostate specific antigen nadir was 0.7 ng/ml for radiation alone and 0.1 ng/ml for radiation plus androgen deprivation therapy. The prostate specific antigen nadir (adjusted HR 1.18/ng/ml increase, 95% CI 1.07-1.31, p=0.001) and Gleason 8 or greater (adjusted HR 8.05, 95% CI 1.01-64.05, p=0.049) significantly predicted increased prostate cancer specific mortality. Moderate/severe comorbidity carried a decreased risk (adjusted HR 0.13, 95% CI 0.02-0.96, p=0.045). Higher prostate specific antigen nadir (adjusted HR 1.10/ng/ml increase, 95% CI 1.04-1.17), older age (adjusted HR 1.10/year, 95% CI 1.04-1.15) and interaction between comorbidity score and randomization arm (each p<0.001) increased the all cause mortality risk. Men who achieved a prostate specific antigen nadir of the median value or less had lower estimated prostate cancer specific and all cause mortality at 7 years (3.7% vs 18.3%, p=0.0005 and 31.5% vs 55.0%, p=0.002). Posttreatment prostate specific antigen nadir is significantly associated with the risk of prostate cancer specific and all cause mortality after radiation with or without androgen deprivation therapy. A suboptimal prostate specific antigen nadir may identify candidates for earlier intervention to prolong survival.

MiR-125b Regulation of Androgen Receptor Signaling Via Modulation of the Receptor Complex Co-Repressor NCOR2

Recognition of micro-RNA function and their contribution to the biology of disease has given a new insight into disease mechanisms, with these discoveries potentially improving clinical diagnostic and therapeutic options. miR-125b has been identified as an important regulator in various cancers, including prostate cancer, but the mechanism of this regulation remains incompletely understood. In these studies, the effect of castration on miR-125b serum expression was evaluated in mice, simulating androgen deprivation. Furthermore, miR-125b expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in LNCaP prostate cancer cells treated with the antiandrogen bicalutamide. Using LNCaP cells, the effect of miR-125b modulation on apoptotic protein and NCOR2, a co-repressor of androgen receptor (AR), was examined by Western blot. A 3′-untranslated region (UTR) luciferase-binding assay was performed to confirm that miR-125b targets NCOR2. We found that surgical castration induced an initial increase in the expression of circulating miR-125b in mice, while sham surgery did not. In addition, AR blockade via bicalutamide was associated with the rapid release of miR-125b into the cell culture medium of prostate cancer cells. A previously studied target of miR-125b, a regulator in the apoptotic pathway, BAK1, could not completely account for the role of miR-125b in prostate cancer. Thus, we looked for additional targets of miR-125b and found that NCOR2, which is a repressor of AR, is a direct target of miR-125b. We found that NCOR2 protein expression was blocked by mimics of miR-125b, and a luciferase-binding assay confirmed that NCOR2 is a direct target of miR-125b. Our data provide novel evidence that miR-125b is an important regulator of the AR with specific ramification for the effectiveness of antiandrogens and other hormonal therapies in prostate cancer.

Bone-modifying agents in the treatment of bone metastases in patients with advanced genitourinary malignancies: a focus on zoledronic acid.

Many patients with advanced genitourinary malignancies develop bone metastases, which can lead to potentially debilitating skeletal complications. Moreover, age-related bone loss and cancer treatments such as hormonal therapy for prostate cancer can weaken bone, placing patients at risk for osteoporotic fractures in addition to skeletal-related events (SREs) from bone metastases. Zoledronic acid, a bisphosphonate, is approved worldwide to reduce the risk of SREs in patients with bone metastases from solid tumors or bone lesions from multiple myeloma. Zoledronic acid, although underutilized in genitourinary malignancies, has long been the mainstay of treatment in patients with bone metastases, and can also help preserve bone during anticancer therapy. Recently, denosumab, a monoclonal antibody directed against the receptor activator of nuclear factor kappa-B ligand, was approved in the United States and the European Union for reducing the risk of SREs in patients with bone metastases from solid tumors. Denosumab (at a lower dose) is also approved in the European Union and the United States to treat androgen deprivation-induced bone loss in men with prostate cancer. In addition, preclinical rationale and emerging clinical data suggest that bone-modifying agents may be able to delay disease progression in genitourinary cancers, just as newly developed anticancer treatments have produced reductions in SREs, possibly by indirect effects on the disease course. This review article summarizes current data and ongoing studies to preserve bone health in patients with advanced genitourinary cancers.

Effectiveness and adverse effects of hormonal therapy for prostate cancer: Japanese experience and perspective.

Recently, novel anti-androgens and inhibitors of androgen biosynthesis have been developed through the elucidation of mechanisms of castration resistance of prostate cancer. We believe that these new developments will improve hormonal therapy. On the other hand, there has been an increase in criticism of hormonal therapy, because hormonal therapy is supposed to induce adverse effects such as cardiovascular disease. In this review, we have introduced the Japanese experience of hormonal therapy, because we believe that there may be ethnic differences between Caucasians and Asian people in the efficacy and adverse effects of hormonal therapy. First, we showed that primary hormonal therapy can achieve long-term control of localized prostate cancer in some cases and that quality of life of patients receiving hormonal therapy is rather better than previously thought. Neoadjuvant and adjuvant hormonal therapy in cases undergoing radical prostatectomy or radiotherapy are very useful for high-risk or locally advanced prostate cancer. Further clinical trials are required to confirm the efficacy of neoadjuvant or adjuvant hormonal therapy. We showed that the death from cardiovascular diseases in Japanese patients receiving hormonal therapy was not higher than that in the general population. However, efforts should be made to decrease the adverse effects of hormonal therapy, because life-style change may increase the susceptibility to adverse effects by hormonal therapy even in Japan. Managements of endocrine and metabolic dysfunction, such as diabetes mellitus, are essential. New hormonal compounds such as selective androgen receptor modulators capable of specifically targeting prostate cancer are expected to be developed.

Preclinical Characterization of a Novel Diphenyl Benzamide Selective ERα Agonist for Hormone Therapy in Prostate Cancer

Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT improves overall and disease-free survival rates, but long-term therapy is associated with severe side effects of androgen and estrogen depletion including hot flashes, weight gain, depression, and osteoporosis. Effective hormone reduction can be achieved without estrogen deficiency-related side effects by using therapy with estrogenic compounds. However, cardiovascular complications induced by estrogens coupled with the availability of LHRH agonists led to discontinuation of estrogen use for primary androgen deprivation therapy in the 1980s. New treatments for prostate cancer that improve patient outcomes without the serious estrogen deficiency-related toxicities associated with ADT using LHRH analogs are needed. Herein we describe a novel nonsteroidal selective estrogen receptor-α agonist designed for first-line therapy of advanced prostate cancer that in animal models induces medical castration and minimizes many of the estrogen deficiency-related side effects of ADT. The present studies show that orally administered GTx-758 reversibly suppressed testosterone to castrate levels and subsequently reduced prostate volume and circulating prostate-specific antigen in relevant preclinical models without inducing hot flashes, bone loss, thrombophilia, hypercoagulation, or increasing fat mass.

Nonlinear systems identification by combining regression with bootstrap resampling

A new parameter estimation method for nonlinear systems from time series data is proposed. For the purpose of unbiased estimation, we employ the idea of bootstrap method on regression problems. Our method can be applied into even short and noisy data and is expected to give us a robust estimation. Some benchmarks of estimating chaotic models show its practical applicability. We also try to apply this method to analysis for intermittent hormonal therapy for prostate cancer by using a mathematical model and real clinical data.

Androgen deprivation therapy as adjuvant/neoadjuvant to radiotherapy for high-risk localised and locally advanced prostate cancer: recent developments.

Androgen deprivation therapy (ADT) has traditionally formed the mainstay of treatment for advanced/metastatic prostate cancer (PCa); however, it is now also having an increasingly important role in earlier stages of disease. Indeed, in patients with locally advanced or high-risk localised disease, the addition of neoadjuvant and adjuvant hormone therapy is now considered the standard of care for those men treated with radical radiotherapy. Although luteinising hormone-releasing hormone (LHRH) agonists have been used for many years as ADT, they may be associated with clinical flare and testosterone breakthrough. Newer hormonal agents continue to be developed, such as gonadotropin-releasing hormone antagonists, which reduce testosterone and prostate-specific antigen levels more rapidly than LHRH agonists, without testosterone flare. This review examines ADT use in combination with radiotherapy to improve outcomes in localised or locally advanced disease, and examines some of the latest developments in hormonal therapy for PCa.

Long-term Outcome of a Phase II Trial Combining i n Situ Gene Therapy and Intensity Modulated Radiotherapy With or Without Hormonal Therapy for Prostate Cancer

Long-term Outcome of a Phase II Trial Combining i n Situ Gene Therapy and Intensity Modulated Radiotherapy With or Without Hormonal Therapy for Prostate Cancer

Novel Membrane-associated Androgen Receptor Splice Variant Potentiates Proliferative and Survival Responses in Prostate Cancer Cells

Progression from the androgen-sensitive to androgen-insensitive (or castration-resistant) stage is the major obstacle for sustained effectiveness of hormonal therapy for prostate cancer. The androgen receptor (AR) and its splice variants play important roles in regulating the transcription program essential for castration resistance. Here, we report the identification of a novel AR splice variant, designated as AR8, which is up-regulated in castration-resistant prostate cancer cells. AR8 is structurally different from other known AR splice variants because it lacks a DNA binding domain and therefore, unlikely functions as a transcription factor on its own. Immunofluorescence staining revealed that AR8 was primarily localized on the plasma membrane, possibly through palmitoylation of two cysteine residues within its unique C-terminal sequence. Mutation of these putative palmitoylation sites in AR8 led to loss of its plasma membrane localization. In addition, we demonstrated that overexpression of AR8 in prostate cancer cells promoted association of Src and AR with the EGF receptor in response to EGF treatment and enhanced tyrosine phosphorylation of AR. Conversely, specific knockdown of AR8 expression in prostate cancer cells compromised EGF-induced Src activation and AR phosphorylation. This effect was accompanied with attenuation of proliferation and increased apoptosis in prostate cancer cells cultured in androgen-depleted medium. We also showed that AR8 was required for optimal transcriptional activity of AR in response to treatment of both androgen and EGF. Taken together, our results demonstrate that the membrane-associated AR8 isoform may contribute to castration resistance by potentiating AR-mediated proliferative and survival responses to hormones and growth factors.

Bone mineral density in Jamaican men on androgen deprivation therapy for prostate cancer

BackgroundAndrogen deprivation therapy (ADT) has been reported to reduce the bone mineral density (BMD) in men with prostate cancer (CaP). However, Afro-Caribbeans are under-represented in most studies. The aim was to determine the effect of androgen deprivation therapy (ADT) on the bone mineral density (BMD) of men with prostate cancer in Jamaica.MethodsThe study consisted of 346 Jamaican men, over 40 years of age: 133 ADT treated CaP cases (group 1), 43 hormone-naïve CaP controls (group 2) and 170 hormone naïve controls without CaP (group 3). Exclusion criteria included metastatic disease, bisphosphonate therapy or metabolic disease affecting BMD. BMD was measured with a calcaneal ultrasound and expressed in S.D. units relative to young adult men (T score), according to the World Health Organization definition. Patient weight, height and BMI were assessed.ResultsMean ± sd, age of patients in group 1 (75± 7.4 yrs) was significantly greater than groups 2 and 3 (67 ± 8.1 yrs; 65±12.0 yrs). There was no significant difference in weight and BMI between the 3 groups. . The types of ADT (% of cases, median duration in months with IQR) included LHRH (Luteinizing hormone releasing hormone) analogues (28.6%, 17.9, IQR 20.4), oestrogens (9.8%, 60.5, IQR 45.6) anti-androgens (11.3%, 3.3, IQR 15.2) and orchiectomy (15.7%, 43.4, IQR 63.9). Unadjusted t score of group 1, mean ± sd, (-1.6± 1.5) was significantly less than group 2 (-0.9±1.1) and group 3 (-0.7±1.4), p <0.001. Ninety three (69.9%), 20 (45%) and 75 (42%) of patients in groups 1, 2 and 3 respectively were classified as either osteopenic or osteoporotic (p<0.001). Adjusting for age, there was a significant difference in t scores between groups 1 and 2 as well as between groups 1 and 3 (p<0.001). Compared with oestrogen therapy and adjusting for duration of therapy, the odds of low bone mineral density (osteopenia or osteoporosis) with LHRH analogue was 4.5 (95%CI, 14.3 to 3.4); with anti-androgens was 5.9 (95%CI, 32.7 to 5); with orchiectomy was 7.3 (95%CI, 30 to 5.8) and multiple drugs was 9.2 ((95%CI, 31 to 7.1).ConclusionsADT is associated with lower BMD in Jamaican men on hormonal therapy for prostate cancer.

Hormone therapy for prostate cancer and the risk of stroke: a 5‐year follow‐up study

To examine the 5-year risk of stroke among patients with prostate cancer (PC) receiving androgen deprivation therapy (ADT) in Taiwan, using a population-based dataset. This prospective case-control study used data sourced from the Longitudinal Health Insurance Database. The study included 365 patients with PC; 64 (17.6%) received ADT for more than 1 month. Cox proportional hazards regression was used to evaluate the association between ADT and the risk of stroke during the subsequent 5-year follow-up period, after adjusting for sociodemographic characteristics and hypertension, diabetes, coronary heart disease, heart failure, atrial fibrillation and hyperlipidaemia. In the total sample of 365 patients with PC, 68 (18.6%) patients had strokes during the 5-year follow-up period. These included 11 patients with PC who received ADT (17.2% of all patients who received ADT) and 57 patients who did not receive ADT (18.9% of patients who did not receive ADT). After adjusting for potential confounders, no significant difference in the hazard of stroke was found between patients with PC who did and did not receive ADT (hazard ratio, 1.09; 95% confidence interval, 0.80-1.50). There was no significant difference in the risk of stroke between ethnic Chinese patients with PC who did and did not receive ADT, after adjusting for potential confounders.

Coping with sexual concerns after cancer

This review presents an overview of recent developments in research examining coping with the effects of cancer treatment on sexuality. A search was conducted using PubMed and Web of Knowledge to find papers published or in press in 2010. Papers examining coping efforts, effects of cancer treatment in special populations (e.g., advanced cancer, non-western populations), or on broad dimensions of sexuality, and psychosocial and physiological intervention studies addressing sexual issues in cancer were included. Findings underscore the complex effects of treatments (e.g., hormonal therapy for prostate cancer) on patients' sexuality. Studies suggest that successful coping efforts often occur within the context of the relationship and frequently include a process of adjusting one's concept of sexual function and activity through shifting to thoughts and behaviors that center on intimacy and sexual activities other than intercourse (e.g., 'flexible coping'). Results confirm the importance of sexual issues to individuals with cancer and argue for more research on sexual effects of cancer treatment in understudied populations and further empirical studies examining coping with sexual concerns after cancer. Clinical implications include the need for providers to address the broader range of sexual effects of treatments beyond sexual performance.

Old issues and new perspectives on prostate cancer hormonal therapy: the molecular substratum

Secondary hormonal therapy is a treatment option in patients with castration-resistant prostate cancer (CRPC); however, it is underutilized and is room for optimization and improvement. In this context, androgen receptor (AR) is the Achilles' heel, being critically important and various mechanisms ranging from receptor mutations to secondary signaling pathways are responsible for some of the biological heterogeneity, demanding a multimodal approach. A comprehensive review of the peer-reviewed literature is performed on the topic of molecular mechanisms supporting secondary hormonal therapies, including expanded alternative hormonal therapies for CRPC. Essential concepts in clinical treatment of patients with progression on primary hormonal therapy are maintaining the castrate state, accounting for the intermittency phenomenon and sequentially using oral antiandrogens and adrenolytics heading to androgen depletion microenvironment. Survival prolongation, pain relief or measurable improvement in tumor-related symptoms should be persecuted and are considered to be a tangible benefit of obvious worth to the patient. Understanding the underlying molecular substratum is of paramount importance to hormonal therapy optimization in this context once current androgen-depletion strategies are incomplete, and residual androgens as well as alternative routes contribute to sustained AR activity and disease progression to a lethal phenotype. One or many mechanisms may be playing a role, even within the same patient and lastly are potential targets for treatment. Five fundamental mechanisms mediated through the AR to promote tumor growth (three of which depend on ligand signaling) added to the stem cell pathway must be recognized in CRPC. They are persistence of intratumoral androgens as a result of in situ steroidogenesis or adrenal source; AR mutations that allow promiscuous activation by otherwise nonsignaling ligands; wild-type AR gene amplification; alterations in AR coactivator-to-corepressor ratio that impact transcription; outlaw AR pathways that bypass the need for androgens by signaling through crosstalk with other ligand-bound receptors, cytokines, or transactivation of activated tyrosine kinase receptors in the cytosol.

Denosumab

Denosumab (Prolia®) [1, 2] offers a new approach in the treatment of osteoporosis. It decreases bone resorption by inhibiting osteoclast formation, function and survival. The current indication covers osteoporosis in postmenopausal women at increased risk of fracture and men receiving hormonal therapy for prostate cancer. Osteoporosis is characterized by an imbalance between bone formation and bone resorption. The latter process is performed by osteoclasts and occurs at a higher rate in osteoporosis. Receptor activator of nuclear factor-κB ligand (RANKL) is an essential factor in osteoclast differentiation, activation and survival. RANKL, a member of the tumour necrosis factor (TNF) superfamily, is expressed on the osteoblast membrane and binds to receptor activator of nuclear factor-κB (RANK, the receptor) on the osteoclast membrane (Figure 1). Osteoprotegerin (OPG) is the endogenous regulator of this RANKL-mediated activation of osteoclasts. OPG is a soluble RANKL-binding protein that binds RANKL, preventing it from combining with RANK on the osteoclast membrane and thus inhibiting its action. RANK is a membrane-bound, TNF-like receptor that recognizes RANKL through direct cell-to-cell interaction with osteoblasts. Pathophysiology of osteoporosis. Osteoporosis is characterized by a higher rate of bone resorption compared with bone formation. Bone resorption requires differentiation and activation of osteoclasts. Receptor activator of nuclear factor-κB ligand (RANKL) is an essential, stimulating factor in this regulatory process. Binding of RANKL (expressed on the osteoblast membrane) to its receptor activator of nuclear factor-κB (RANK, the receptor) in the osteoclast membrane triggers osteoclast activation and leads to bone resorption. Osteoprotegerin (OPG) is a soluble RANKL receptor and thus acts as an endogenous inhibitor of this RANKL-mediated activation process Denosumab is a human monoclonal IgG2 antibody that binds RANKL with high affinity and specificity, preventing interaction with RANK on the osteoclast membrane (Figure 2). Thus, it mimics endogenous OPG. By attaching to and blocking RANKL, denosumab inhibits osteoclast differentiation, activation and survival. This favours bone formation over bone resorption, increasing bone mass and reducing the risk of fractures [3]. Mechanism of action of denosumab. Denosumab binds to RANKL thereby preventing interaction with RANK on the osteoclast membrane. By attaching to and blocking RANKL, denosumab inhibits osteoclast differentiation and activation. This mechanism of action decreases bone resorption which leads to improved bone density Denosumab is administered once every 6 months as a 60-mg subcutaneous injection. During treatment, calcium and vitamin D supplementation is important. Hypocalcaemia is not a concern during denosumab therapy when patients are adequately supplemented with calcium and vitamin D. Patients with hypocalcaemia and/or chronic kidney disease may develop symptomatic hypocalcaemia upon treatment with denosumab. Therefore, hypocalcaemia should be corrected before therapy and serum calcium concentration monitored. A dental check and treatment if needed may be advised before starting treatment because of a risk of osteonecrosis of the jaw. Because RANKL also has a function in the immune system denosumab could adversely influence infections of the urinary and upper respiratory tracts. Cataracts were observed in men receiving treatment for prostate cancer but a mechanism has not been elucidated and the findings may be coincidental. The development and progression of cataracts will be studied prospectively in planned clinical studies [4].

Intermittent hormonal therapy for prostate cancer

Intermittent hormonal therapy (IHT) for prostate cancer aims to minimize treatment-related side-effects, to improve overall quality of life, to reduce the cost of care, and possibly to delay progression to castration-resistant prostate cancer. With preclinical evidence suggesting a potential benefit for IHT in terms of time to androgen independence, with phase II and phase III studies producing optimistic results, and with the potential for reductions in cost and complications, IHT has become a popular modality of therapy around the globe. In the near future intermittent therapy will have place in the treatment strategy in the management of prostate cancer, particularly on men with locally advanced disease.

Beyond Hormone Therapy for Prostate Cancer with PARP inhibitors

In this issue of Cancer Cell , Brenner et al. describe that the poly-(ADP) ribose polymerase (PARP) may mediate ERG function and that PARP blockade has antitumor activity in ETS gene-rearranged prostate cancer models. These data support the clinical evaluation of PARP inhibitors for treating ETS gene-rearranged prostate cancers.

Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space.

Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC). Despite this designation, however, there is evidence that androgen receptor (AR)-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands. The therapeutic options were limited and palliative in nature until trials in 2004 demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC. After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel (with prednisone), or treatment with the antiandrogen abiraterone (with prednisone) could improve survival for patients with mCRPC following docetaxel therapy. Compared with mitoxantrone/prednisone, cabazitaxel/prednisone significantly improved overall survival, with a 30% reduction in rate of death, in patients with progression of mCRPC after docetaxel therapy in the TROPIC trial. Similarly, abiraterone acetate (an inhibitor of androgen biosynthesis) plus prednisone significantly decreased the rate of death by 35% compared with placebo plus prednisone in mCRPC patients progressing after prior docetaxel therapy in the COU-AA-301 trial. Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space." In view of the continued AR-mediated signaling on mCRPC, results from additional phase 3 studies with novel antiandrogens which are directed at inhibition of the AR (e.g., MDV3100), as well as other agents, are awaited with interest and may further expand the treatment choices for this difficult-to-manage population of patients.