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Identification of favorable subgroups for alternative anti-androgen therapy in castration-resistant prostate cancer.

ABSTRACT: Although alternative anti-androgen therapy (switching to secondary anti-androgens) is no longer recommended in the clinical guidelines of prostate cancer in light of the new hormonal and cytotoxic agents available, this therapy has proven beneficial for some patients with castration-resistant prostate cancer (CRPC). The objective of this study was to identify favorable subgroups for alternative anti-androgen therapy among CRPC patients. Eighty-eight consecutive CRPC patients treated with alternative anti-androgen therapy were included in this study. All patients were treated with bicalutamide in the initial maximum androgen blockade (MAB) and switched to flutamide in the subsequent alternative anti-androgen therapy, combined with a luteinizing hormone-releasing hormone analogue. Several clinical and pathological factors for predicting the prostate-specific antigen (PSA) decline and PSA progression-free survival (PSA-PFS) of alternative anti-androgen therapy were investigated. Of all patients, 45 (51.1%) patients showed ?50% PSA decline. The median PSA-PFS was 7.5 months [95% confidence interval (CI), 5.7-10.3]. Notably, 15 (17.0%) patients had a PSA-PFS over 2 years. A multivariate analysis showed that ?3 bone metastatic lesions and a duration <12 months of initial MAB were significant factors shortening the duration of PSA-PFS, with hazard ratios of 2.11 (95% CI, 1.23-3.62; P=0.007) and 2.08 (95% CI, 1.20-3.57; P=0.008), respectively. Patients without any of these factors had a median PSA-PFS of 22.8 months (95% CI, 6.7-48.8). The overall survival in patients with a ?7.5-month PSA-PFS receiving alternative anti-androgen therapy was significantly longer than that of patients with a <7.5-month PSA-PFS (109.1 vs. 40.8 months; P<0.001). In conclusion, a longer duration of initial MAB and the absence of severe bone metastasis may predict a favorable response to alternative anti-androgen therapies in CRPC patients. Alternative anti-androgen therapy may still be beneficial for these patients, but this needs to be investigated further.

SUBMITTER: Suzuki K

PROVIDER: S-EPMC6787950 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Identification of favorable subgroups for alternative anti-androgen therapy in castration-resistant prostate cancer.

Suzuki Kotaro K Terakawa Tomoaki T Shigemura Katsumi K Furukawa Junya J Harada Kenichi K Hinata Nobuyuki N Nakano Yuzo Y Fujisawa Masato M

Molecular and clinical oncology 20190827 5

Although alternative anti-androgen therapy (switching to secondary anti-androgens) is no longer recommended in the clinical guidelines of prostate cancer in light of the new hormonal and cytotoxic agents available, this therapy has proven beneficial for some patients with castration-resistant prostate cancer (CRPC). The objective of this study was to identify favorable subgroups for alternative anti-androgen therapy among CRPC patients. Eighty-eight consecutive CRPC patients treated with alterna ...[more]

PMID: 31620284

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Project description:Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR) is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the androgen/ligand binding site. Unfortunately, with the inevitable progression of the cancer to castration resistance, many of these drugs become ineffective. However, there are numerous other regulatory sites on this protein that have not been exploited therapeutically. The regulation of AR activity involves a cascade of complex interactions with numerous chaperones, co-factors and co-regulatory proteins, leading ultimately to direct binding of AR dimers to specific DNA androgen response elements within the promoter and enhancers of androgen-regulated genes. As part of the family of nuclear receptors, the AR is organized into modular structural and functional domains with specialized roles in facilitating their inter-molecular interactions. These regions of the AR present attractive, yet largely unexploited, drug target sites for reducing or eliminating androgen signaling in prostate cancers. The design of small molecule inhibitors targeting these specific AR domains is only now being realized and is the culmination of decades of work, including crystallographic and biochemistry approaches to map the shape and accessibility of the AR surfaces and cavities. Here, we review the structure of the AR protein and describe recent advancements in inhibiting its activity with small molecules specifically designed to target areas distinct from the receptor's androgen binding site. It is anticipated that these new classes of anti-AR drugs will provide an additional arsenal to treat castration-resistant prostate cancer.

Project description:ContextSecond-generation androgen receptor inhibitors (ARIs) extend metastasis-free survival, prolong overall survival, and delay symptoms when added to androgen deprivation therapy for the treatment of castration-sensitive or castration-resistant prostate cancer (CRPC). However, ARIs may adversely impact physical and cognitive function, thereby decreasing quality of life and prognosis.ObjectiveTo evaluate the evidence regarding the potential effects of ARIs on physical and cognitive function and to contextualize how drug-related adverse effects may influence treatment decisions in CRPC.Evidence acquisitionWe performed a literature search using MEDLINE from January 1998 to June 2020 using terms relating to prostate cancer, androgen deprivation, and physical and cognitive function. We selected 61 publications for analysis.Evidence synthesisTreatment-induced deterioration in physical and cognitive function may impair the independence and well-being of patients with CRPC. Patient-reported outcomes from clinical trials of ARIs provide quantitative evidence of their impact on these domains, which appears to vary between ARIs, reflecting the different adverse event profiles of these agents. Thus, the risk of physical or cognitive dysfunction may be managed or mitigated by appropriate selection of treatment options. Studies in patients with CRPC have assessed the cognitive effects of ARIs with validated instruments, whereas quantitative analysis of the impact on physical function has been limited.ConclusionSeveral validated instruments utilized for the assessment of physical and cognitive function in clinical studies have been adapted for clinical practice; however, consensus on the standardization of these assessments is required. Future clinical studies employing validated tools may generate data on the impact of ARIs and guide treatment decisions for patients with CRPC.Patient summaryWe review the hormonal therapies used to treat men with prostate cancer and the effects they have on physical and cognitive function. We discuss how to measure these effects and how this may assist when choosing treatment.

Project description:BACKGROUND:Multiple androgens drive prostate cancer progression and higher pre-treatment levels of androgens, even within the castrate range, have been previously shown to be associated with an improved overall survival (OS) in mCRPC. Docetaxel impairs microtubules, has androgen receptor (AR) inhibitory effects and is used in both the castration resistant and sensitive settings, where androgen dynamics may impact outcome. The present analysis evaluates the association of decline in serum androgen levels (Testosterone (T), Androstenedione (A) and DHEA in docetaxel-treated mCRPC patients with OS. METHODS:Data from 1050 men treated on CALGB 90401 with docetaxel, prednisone and either bevacizumab or placebo were evaluated. Eligibility required progressive mCRPC and no prior chemotherapy. Pre-treatment, 6 week and progression serum assays for T, A and DHEA were performed via tandem Liquid Chromatography-Mass Spectrometry (LC-MS/MS). Changes in T, A and DHEA levels from baseline to 6 weeks were calculated as the ratio of 6-week over baseline. The proportional hazards model was used to assess the prognostic significance of changes in T, A, and DHEA from baseline to 6 weeks in predicting OS adjusting for known prognostic factors. RESULTS:Median baseline values for T, A, and, DHEA were 1.0, 13.5, and 8.1?ng/dL respectively while 6 week levels were 0.64, 7.0, and 6.8?ng/dL respectively. Median OS for low testosterone decline is 20.9 months vs 26.3 months for high testosterone decline. In multivariable analysis including known prognostic variables, change in testosterone levels was independently associated with greater OS; the hazard ratio for death with each unit increase in the 6-week/baseline ratio is 1.02 (95% CI?=?1.01-1.03, p?=?0.001). Decline in A and DHEA were not significant predictors of OS. In multivariable analysis change in the serum changes did not predict PFS however the ratio of T at 6-weeks over baseline was prognostic of ?50% decline in PSA with an odds ratio of 0.93 (95% CI?=?0.85-0.98, p-value?=?0.039). CONCLUSIONS:Declines in testosterone during docetaxel treatment is associated with a longer survival, consistent with a favorable prognostic significance of higher serum androgens in the CRPC.

Dataset Information

Identification of favorable subgroups for alternative anti-androgen therapy in castration-resistant prostate cancer.

Publications

Identification of favorable subgroups for alternative anti-androgen therapy in castration-resistant prostate cancer.

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