Emerging Treatments for Castrate-Resistant Prostate Cancer

2011 ◽  
Vol 24 (4) ◽  
pp. 366-373
Author(s):  
Michell B. Redding ◽  
Minal Surati
Keyword(s):  
Prostate Cancer ◽  
Antitumor Agents ◽  
Specific Antigen ◽  
Abiraterone Acetate ◽  
Cytotoxic Agents ◽  
Emerging Treatments ◽  
Castrate Resistant Prostate Cancer ◽  
New Treatment ◽  
Castrate Resistant ◽  
Androgen Depletion

Castrate-resistant prostate cancer (CRPC) is a challenging aspect in the treatment of prostate cancer. Research has identified several pathways in the pathogenesis of CRPC. Several new agents targeting some of these pathways have shown promising data during clinical trials. In the area of androgen depletion, abiraterone acetate and MDV100 have been studied and have shown to decrease prostate-specific antigen (PSA) levels in phase I and II studies. Bevacizumab is a monoclonal antibody antiangiogenesis agent that targets vascular endothelial growth factor (VEGF) and has shown to decrease PSA levels in combination with other cytotoxic agents. Three agents, ixabepilone, patupilone, and sagopilone, in the class of epothilones (tubulin polymerizing antitumor agents), have shown moderate reductions in PSA levels and moderate adverse effects. The results of ongoing studies with these new treatment agents may offer viable alternatives to the traditional treatment of CRPC to decrease disease progression and improve overall survival.

Biomarker development trial of satraplatin in patients with metastatic castrate-resistant prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 170-170
Author(s):  
Bobby Chi-Hung Liaw ◽  
Sonia Maria Seng ◽  
Matt D. Galsky ◽  
Che-Kai Tsao ◽  
Phillip G. Febbo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Genomic Analysis ◽  
Predictive Biomarkers ◽  
Cytotoxic Agents ◽  
Fourth Generation ◽  
Tissue Samples ◽  
Castrate Resistant Prostate Cancer ◽  
Pre Treatment ◽  
Castrate Resistant

170 Background: While satraplatin, a fourth generation oral platinum analogue, failed to improve overall survival (OS) in an unselected metastatic castrate-resistant prostate cancer (mCRPC) population (Sternberg, JCO 2009), anti-tumor activity was demonstrated, suggesting a “platinum-sensitive” subset of patients. Predictive biomarkers may not only select patients most likely to benefit from novel “targeted” therapies but also from standard (even discarded) cytotoxic agents. Development of predictive biomarkers in mCRPC is hampered by the fact that PC is associated with a long natural history and evolving genetic changes, highlighting the need for immediate pre-treatment metastatic tissue samples for biomarker development. In this trial, we sought to determine the feasibility of obtaining metastatic biopsies in patients with mCRPC treated with satraplatin. Methods: Docetaxel-refractory mCRPC patients underwent image-guided biopsy of metastatic lesions prior to treatment with satraplatin 80 mg/m2 PO on days 1 to 5 of a 35-day cycle and prednisone 5 mg PO twice daily. Biopsy samples are analyzed by whole exome and RNA sequencing, and peripheral blood samples are undergoing transcriptional profiling, to facilitate biomarker development. Results: Thirteen patients were enrolled with a median age of 71 (range: 55 to 80), prostate-specific antigen (PSA) of 82 ng/ml (0.04-3057), and Gleason score 8 (7 to 9). All patients received prior docetaxel, four (31%) had more than or eqaul to two prior chemotherapies, and two (15%) received abiraterone. Drug-related grade 3/4 toxicities included leukopenia (23%), neutropenia (8%), thrombocytopenia (8%), fatigue (8%), renal failure (8%), dysphagia (17%), and diarrhea (8%). A median of four cycles of satraplatin were completed, with declines of serum PSA of greater than or equal to 30% achieved in 4 of 13 patients (31%; 95% CI, 57.3 to 85.4%). Median time to PSA progression was 12.4 weeks (95% CI, 7.2 to 29.7+ weeks). Metastatic pre-treatment biopsies were collected in all study patients; genomic analysis is ongoing. Conclusions: This study confirms that satraplatin has anti-cancer activity in a subset of patients with mCRPC. Trials that require pre-treatment metastatic tumor biopsies are feasible. Analysis of the correlation between molecular signatures and treatment response will be presented at the meeting. Clinical trial information: NCT01289067.

scholarly journals Identification of subgroups of metastatic castrate-resistant prostate cancer (mCRPC) patients treated with abiraterone plus prednisone at low- vs. high-risk of radiographic progression: An analysis of COU-AA-302

2018 ◽  
Vol 13 (6) ◽  
Author(s):  
Lisa J. Martin ◽  
Shabbir M.H. Alibhai ◽  
Maria Komisarenko ◽  
Narhari Timilshina ◽  
Antonio Finelli
Keyword(s):  
Prostate Cancer ◽  
Radiographic Progression ◽  
Proportional Hazards ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Limited Resource ◽  
Abiraterone Acetate ◽  
Cox Proportional Hazards ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

Introduction: Radiographic imaging is used to monitor disease progression for men with metastatic castrate-resistant prostate cancer (mCRPC). The optimal frequency of imaging, a costly and limited resource, is not known. Our objective was to identify predictors of radiographic progression to inform the frequency of imaging for men with mCRPC. Methods: We accessed data for men with chemotherapy-naive mCRPC in the abiraterone acetate plus prednisone (AA-P) group of a randomized trial (COU-AA-302) (n=546). We used Cox proportional hazards modelling to identify predictors of time to progression. We divided patients into groups based on the most important predictors and estimated the probability of radiographic progression-free survival (RPFS) at six and 12 months. Results: Baseline disease and change in prostate-specific antigen (PSA) at eight weeks were the strongest determinants of RPFS. The probability of RPFS for men with bone-only disease and a ≥50% fall in PSA was 93% (95% confidence interval [CI] 87–96) at six months and 80% (95% CI 72–86) at 12 months. In contrast, the probability of RPFS for men with bone and soft tissue metastasis and <50% fall in PSA was 55% (95% CI 41–67) at six months and 34% (95% CI 22–47) at 12 months. These findings should be externally validated. Conclusions: Patients with chemotherapy-naive mCRPC treated with first-line AA-P can be divided into groups with significantly different risks of radiographic progression based on a few clinically available variables, suggesting that imaging schedules could be individualized.

scholarly journals Effects of Abiraterone Acetate on Androgen Signaling in Castrate-Resistant Prostate Cancer in Bone

2012 ◽  
Vol 30 (6) ◽  
pp. 637-643 ◽  
Author(s):  
Eleni Efstathiou ◽  
Mark Titus ◽  
Dimitra Tsavachidou ◽  
Vassiliki Tzelepi ◽  
Sijin Wen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Marrow ◽  
Bone Marrow Aspirate ◽  
Specific Antigen ◽  
Abiraterone Acetate ◽  
Open Label ◽  
Clinical Observations ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Tumor Expression

Purpose Persistent androgen signaling is implicated in castrate-resistant prostate cancer (CRPC) progression. This study aimed to evaluate androgen signaling in bone marrow–infiltrating cancer and testosterone in blood and bone marrow and to correlate with clinical observations. Patients and Methods This was an open-label, observational study of 57 patients with bone-metastatic CRPC who underwent transiliac bone marrow biopsy between October 2007 and March 2010. Patients received oral abiraterone acetate (1 g) once daily and prednisone (5 mg) twice daily. Androgen receptor (AR) and CYP17 expression were assessed by immunohistochemistry, testosterone concentration by mass spectrometry, AR copy number by polymerase chain reaction, and TMPRSS2-ERG status by fluorescent in situ hybridization in available tissues. Results Median overall survival was 555 days (95% CI, 440 to 965+ days). Maximal prostate-specific antigen decline ≥ 50% occurred in 28 (50%) of 56 patients. Homogeneous, intense nuclear expression of AR, combined with ≥ 10% CYP17 tumor expression, was correlated with longer time to treatment discontinuation (> 4 months) in 25 patients with tumor-infiltrated bone marrow samples. Pretreatment CYP17 tumor expression ≥ 10% was correlated with increased bone marrow aspirate testosterone. Blood and bone marrow aspirate testosterone concentrations declined to less than picograms-per-milliliter levels and remained suppressed at progression. Conclusion The observed pretreatment androgen-signaling signature is consistent with persistent androgen signaling in CRPC bone metastases. This is the first evidence that abiraterone acetate achieves sustained suppression of testosterone in both blood and bone marrow aspirate to less than picograms-per-milliliter levels. Potential admixture of blood with bone marrow aspirate limits our ability to determine the origin of measured testosterone.

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