Abiraterone In Prostate Cancer Research Articles

Effect of prednisone dosing on mineralocorticoid-related side effects with abiraterone in prostate cancer.

67 Background: Abiraterone, a 17a hydroxylase inhibitor, is used for prostate cancer and can lead to mineralocorticoid excess syndrome (e.g. hypertension and hypokalemia). Concurrent prednisone mitigates these effects; however, the optimal prednisone dosage is unclear. This study examines the occurrence of mineralocorticoid side effects from Abiraterone with 5 mg of prednisone daily versus 5 mg twice daily. Methods: Data for 1410 patients treated with abiraterone from 2011 to 2022 were identified from a large academic/community hospital system (Health Data Compass Data Warehouse project). Laboratory measures, clinical parameters, and ICD10 codes were collected from 6 months prior to abiraterone initiation through treatment duration. 348 patients were excluded for missing medication data, discordant prednisone initiation, and use of a second steroid; 1062 patients remained (5 mg daily, N = 555, 10 mg daily, N = 507). Prednisone dose was treated as a time-varying covariate due to dose-switching (N = 122). Hypokalemia and hypertension incidence over 24 weeks after abiraterone initiation was analyzed via time to event frailty cox-proportional hazard models using both CTCAE v5.0 grade and ICD 10 code outcomes. Results: Patients on 5 mg of prednisone twice daily had approximately a 96% longer average time to first event for a combined-endpoint of hypertension and hypokalemia via ICD10 code methodology at any point during the 24 weeks following abiraterone initiation (HR 0.51, CI 0.43 - 0.62, P < 0.001). This trend was durable with individual ICD10 analysis in hypertension (HR 0.52, CI 0.43 - 0.62, P < 0.001) and hypokalemia (HR 0.45, CI 0.30 - 0.66, P = <0.001). Assessing direct clinical measurements via incidentally recorded blood pressure and potassium lab values, the analysis for grade 2/3 hypertension (HR 0.81, CI 0.7-0.93, P = 0.004) and grade 3 hypokalemia (HR 0.46, CI 0.26-0.82, P = 0.008) also showed a corresponding increase in average time to first measure favoring the 5 mg twice daily cohort during the 24-week period. Conclusions: This study shows a significant delay in the development of hypertension and hypokalemia from abiraterone with 5 mg twice daily compared to 5 mg of prednisone daily. This was observed both with ICD10 coding and direct clinical measurements of these events within the EMR. Assessments of other physiologic parameters and survival are ongoing. These findings highlight the impact of prednisone dosing with abiraterone, which may merit additional consideration in specific at-risk patient populations including those with baseline hypertension or cardiovascular risk factors.

Major adverse cardiovascular events of enzalutamide versus abiraterone in prostate cancer: a retrospective cohort study

BackgroundWhile the cardiovascular risks of androgen receptor pathway inhibitors have been studied, they were seldom compared directly. This study compares the risks of major adverse cardiovascular events (MACE) between enzalutamide and abiraterone among prostate cancer (PCa) patients.MethodsAdult PCa patients receiving either enzalutamide or abiraterone in addition to androgen deprivation therapy in Hong Kong between 1 December 1999 and 31 March 2021 were identified in this retrospective cohort study. Patients who switched between enzalutamide and abiraterone, initiated abiraterone used without steroids, or experienced prior cardiac events were excluded. Patients were followed-up until 30 September 2021. The primary outcomes were MACE, a composite of stroke, myocardial infarction (MI), Heart failure (HF), or all-cause mortality and a composite of adverse cardiovascular events (CACE) not including all-cause mortality. The secondary outcomes were individual components of MACE. Inverse probability treatment weighting was used to balance covariates between treatment groups.ResultsIn total, 1015 patients were analyzed (456 enzalutamide users and 559 abiraterone users; mean age 70.6 ± 8.8 years old) over a median follow-up duration of 11.3 (IQR: 5.3–21.3) months. Enzalutamide users had significantly lower risks of 4P-MACE (weighted hazard ratio (wHR) 0.71 [95% confidence interval (CI) 0.59–0.86], p < 0.001) and CACE (wHR 0.63 [95% CI: 0.42–0.96], p = 0.031), which remained consistent in multivariable analysis. Such an association may be stronger in patients aged ≥65 years or without diabetes mellitus and was independent of bilateral orchidectomy. Enzalutamide users also had significantly lower risks of MI (wHR 0.57 [95% CI: 0.33–0.97], p = 0.040) and all-cause mortality (wHR 0.71 [95% CI: 0.59–0.85], p < 0.001).ConclusionEnzalutamide was associated with lower cardiovascular risks than abiraterone in PCa patients.

P099 - Low dose abiraterone in prostate cancer - safety, efficacy and pharmacoeconomic implications

P099 - Low dose abiraterone in prostate cancer - safety, efficacy and pharmacoeconomic implications

Abstract A083: Low dose abiraterone in prostate cancer - Safety, efficacy and pharmacoeconomic implications

Abstract Background and aim: Survival has improved in metastatic castration-resistant prostate cancer (mCRPC) because of the development of effective drugs such as abiraterone acetate, but universal accessibility to treatment is not always possible because of cost constraints in lower- and middle-income countries. Abiraterone in fasting state is the standard of care in mCRPC. Despite a large food effect, it was administered under fasting conditions in its pivotal trials. Recently, the National Comprehensive Cancer Network (NCCN) has included low-dose abiraterone (250 mg/day) with food as an alternative treatment option to full-dose abiraterone (1,000 mg/day) fasting. This translates to 75% cost reduction. This study aims to find safety, efficacy and pharmacoeconomic implications of low dose abiraterone in mCRPC. Materials and Methods: In this cohort study mCRPC Patients with progression were offered low dose abiraterone with low fat meal along with prednisone 5 mg twice daily. Prostate-specific antigen (PSA) was assessed monthly and toxicity assessment was made every week. Final PSA response (≥ 50% reduction) and toxicity assessment were done at 12 weeks. In case of grade IV toxicity (Anemia, Hypertension, Hypokalemia, Hypocalcemia – CTC AE V5.0) because of higher drug bioavailability, patient would be offered full dose abiraterone. 10 patients were offered low dose abiraterone in 2022. Results: 6 out of 10 patients achieved desired PSA response at 12 weeks which is a bit on higher side compared to standard dose abiraterone (recent literature). Fortunately, none of the patient developed grade IV toxicity. This finding was assuring, and no patient shifted to standard dosing. Conclusions: Low dose abiraterone (with low-fat breakfast) is noninferior to full dose abiraterone with respect to PSA metrics. Toxicity is the major thing to look at and given the pharmacoeconomic implications it’s imperative to adopt this strategy in places where affordability is the issue. Let the patients have something rather than nothing! Citation Format: Suryakanta Acharya. Low dose abiraterone in prostate cancer - Safety, efficacy and pharmacoeconomic implications [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A083.

Metastatic prostate cancer management: 20 years of progress

Since 1940, patients with metastatic prostate cancer were given androgen deprivation therapy alone. In 2013, the addition of docetaxel improved progression-free survival and overall survival in patients with metastatic hormone-sensitive prostate cancer. 1 Gravis G Fizazi K Joly F et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013; 14: 149-158 Summary Full Text Full Text PDF PubMed Scopus (528) Google Scholar , 2 Sweeney CJ Chen YH Carducci M et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015; 373: 737-746 Crossref PubMed Scopus (1831) Google Scholar After 2013, the combination of abiraterone acetate plus prednisolone with androgen deprivation therapy increased overall survival, as did the addition of other androgen receptor signalling inhibitors (such as enzalutamide or apalutamide) to standard androgen deprivation therapy. 3 James ND de Bono JS Spears MR et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017; 377: 338-351 Crossref PubMed Scopus (1091) Google Scholar , 4 Davis ID Martin AJ Stockler MR et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019; 381: 121-131 Crossref PubMed Scopus (734) Google Scholar , 5 Chi KN Chowdhury S Bjartell A et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021; 39: 2294-2303 Crossref PubMed Scopus (124) Google Scholar In 2022, the triple combination of androgen deprivation therapy, docetaxel, and abiraterone or darolutamide showed improved overall survival compared with androgen deprivation therapy plus docetaxel. 6 Fizazi K Foulon S Carles J et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022; 399: 1695-1707 Summary Full Text Full Text PDF PubMed Scopus (112) Google Scholar , 7 Smith MR Hussain M Saad F et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022; 386: 1132-1142 Crossref PubMed Scopus (153) Google Scholar Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocolEnzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. Full-Text PDF Open Access

Major adverse cardiovascular events of enzalutamide versus abiraterone in prostate cancer: A prospective cohort study

Major adverse cardiovascular events of enzalutamide versus abiraterone in prostate cancer: A prospective cohort study

AKT1 regulates UHRF1 protein stability and promotes the resistance to abiraterone in prostate cancer

Oncogenic activation of PI3K/AKT signaling pathway, together with epigenetic aberrations are the characters of castration-resistant prostate cancer (CRPC). UHRF1 as a key epigenetic regulator, plays a critical role in prostate cancer (PCa) development, and its expression is positively correlated with the degree of malignancy. In this present study we investigated the potential regulatory mechanism of AKT1 on UHRF1, and further validated the in vitro and in vivo anticancer efficacy of AKT phosphorylation inhibitor MK2206 in combination with abiraterone. Both UHRF1 and p-AKT aberrantly overexpressed in the abiraterone-resistant PCa cells. Further studies revealed that AKT1 protein interacts with UHRF1, and AKT1 directly phosphorylates UHRF1 via the site Thr-210. MK2206 induced UHRF1 protein degradation by inhibiting AKT1-induced UHRF1 phosphorylation, and then reduced the interaction between UHRF1 and deubiquitinase USP7, while promoted the interaction between UHRF1 and E3 ubiquitin protein ligase BTRC. MK2206 significantly promoted the sensitivity of abiraterone-refractory PCa cells and xenografts to abiraterone by decreasing UHRF1 protein level, and reversed the phenotype of NEPC, evently induced cellular senescence and cell apoptosis. Altogether, our present study for the first time revealed a novel molecular mechanism of abiraterone resistance through PI3K/AKT-UHRF1 pathway, and provided a novel therapeutic modality by targeting PI3K/AKT1 to promote the drug sensitivity of abiraterone in PCa patients.

170P Safety, efficacy and pharmacoeconomic implications of low dose abiraterone in prostate cancer

1.4 million new prostate cancer cases were detected in 2020. Survival has improved in metastatic castration-resistant prostate cancer (mCRPC) because of the development of effective drugs such as abiraterone acetate, but universal accessibility to treatment is not always possible because of cost constraints in lower- and middle-income countries. Abiraterone in fasting state is the standard of care in mCRPC. Despite a large food effect, it was administered under fasting conditions in its pivotal trials.

Reduced utilisation and costs with enzalutamide vs abiraterone in prostate cancer

Reduced utilisation and costs with enzalutamide vs abiraterone in prostate cancer

Docetaxel cost-saving alternative to abiraterone in prostate cancer

Docetaxel cost-saving alternative to abiraterone in prostate cancer

Abstract SY31-03: Predictive biomarkers in circulating tumor cells to direct management metastatic castration-resistant prostate cancer (mCRPC)

Abstract Tissue and cfDNA NGS profiling is improving our ability to detect and clinically validate the significance of molecular alterations that drive tumor growth resulting in actionable therapeutic strategies that can improve outcomes for subsets of patients and accelerate the regulatory approval of targeted agents. Confounding our knowledge base are three critical aspects: 1) intra patient and intra-tumor heterogeneity for which the clustering of alterations and signaling pathways cannot be easily disassociated without cellular context, 2) epigenetic and functional cellular biology alterations which perturb genomic pathways presumed to drive tumor growth, and 3) understanding the clinical significance of “variants of uncertain significance” (with respect to changes in protein function) (1) (https://www.ncbi.nlm.nih.gov/pubmed/26582918). Our objective is to improve the outcomes for men with mCRPC starting by identifying unmet needs at decision points in management, credentialing biomarkers to better inform the decision, followed by the analytical and clinical validation of the assay and the biomarker in a sequence of trials in which samples are obtained at the decision point and associated with outcomes, and showing that use of the test result to direct management improves patient outcomes compared to non-use of the test. Our focus is on predictive biomarkers of sensitivity and resistance assessed at the level of the single circulating tumor cell (CTC) through Functional Cell Profiling (FCP) analyzed by 1) protein characterization &amp; localization, 2) cellular and sub-cellular morphology aggregated with machine learned CTC profiles, and 3) low pass whole genome copy number changes. Establishing a phenotype genotype relationship enables a rapid turnaround of test results to inform decision making for an individual patient. Building on the initial results reported by Investigators at JHU (2) showing the association of the presence of the ARV7 (androgen receptor splice variant 7) in CTC using a PCR based assay predicted for resistance to androgen receptor signaling inhibitors (ARSI) but not taxane based chemotherapy, we applied a protein based assay that enabled distinguishing the localization of the splice variant, nuclear vs. cytoplasmic that showed increased specificity, resistance to ARSI, and clinical utility based on a treatment specific interaction that showed in a survival benefit for treatment with a taxane for patients with AR-V7+ CTC (3, 4). The assay, now marketed, has also received a favorable coverage determination from CMS. Later, building on the regulatory precedent for image based phenotyping that enabled rapid cervical cancer screening, we analyzed CTCs based on protein expression and localization and digital pathology features similar to what is applied in facial recognition analyses, to define phenotypically unique cell type (5), studied independently for the relationship to sensitivity to standard of care (SOC) drugs. The aim was to enable rapid test turnaround to enable real time treatment selection decisions. Such profiling has identified unique cell types associated with resistance to ARSi’s and taxanes, and single cell genomic analyses confirmed differences between cell types, providing insight into the underlying mechanisms. More recently we have focused on the development of a phenotypic biomarker of genomic instability, an important driver of tumor progression, that utilizes morphology to identify CTCs with an abnormal number of single cell Large Scale Transitions (LSTs). The resultant biomarker, phenotypic LST (pLST), was then examined in patient CTCs prior to and shortly after treatment with an ARSI or taxane. Those determined to be pLST biomarker positive have worse OS than those who don’t. An important aspect of liquid biopsy analysis is the biologic characterization of the cells that persist, i.e. that are resistant de novo, and which emerging during therapy that have acquired resistance to treatment. In the case of CTCs, we have validated through 5 prospective phase III trials that the elimination of all CTCs on therapy portends a better clinical response than those who have residual CTCs (6). In this context, pLST CTC biomarker positivity ~1 mo after the start of therapy portends a poor outcome whereby fewer than 15% of patients survive beyond 1 yr. Importantly however, is that these pLST+ cells are/were eliminated in patients treated with a PARP inhibitor and had improved PSA response rates7, suggesting that specifically targeting genomic instability is a valid approach where other standard of care drugs fail. Functional Cell Profiling or FCP has also provided an improved understanding of the tumor heterogeneity common in many patients, occurrence of discordance between phenotype and genotype, and the greater biologic learnings of single cell analysis. The framework has allowed us to postulate a novel strategy for analyzing CTCs through FCP for prediction of therapeutic benefit and subclonal disease resistance. Characterizing CTCs in individual patients may provide insight into disease evolution, inform treatment decisions for individual patients and guide new drug development. Longitudinal monitoring of phenotypic CTC subtypes in multiple clinical trials is currently underway.

Abstract 334: Proteostasis by HSP70/STUB1 complex regulates androgen receptor variants expression and confers resistance to enzalutamide and abiraterone

Abstract INTRODUCTION AND OBJECTIVES: Proteostasis is a complementary process by which cells control the protein biosynthesis, folding, trafficking and degradation. Evidence suggests that proteomic instability, such as protein misfolding and aggregation plays pivotal roles in cancer cell survival and progression. AR-V7 lacking the ligand binding domain confers resistance to enzalutamide and abiraterone in prostate cancer, targeting AR-V7 is an logical strategy to overcome the resistance. The mechanisms of AR-V7 proteostasis haven’t been fully studied so far. The objectives of this project are to investigate the roles of proteostasis in regulating AR-V7 expression and sensitivity to enzalutamide and abiraterone treatment. METHODS: Expression of HSP70 and STUB1 was determined by qRT-PCR and western blot. Expression of HSP70 and STUB1 was downregulated using specific siRNA. HSP70/STUB1 and AR-V7 interaction was determined by co-immunoprecipitation and dual immunofluorescence. The gene regulating mechanisms underlying the HSP70 inhibition in drug resistant prostate cancer cells was determined by RNA sequencing analyses. The effects of HSP70 inhibition on enzalutamide sensitivity were examined in vitro and in vivo. The correlation between HSP70 and AR-V7 in high Gleason score prostate tumors was determined by qRT-PCR. RESULTS: In the present study, we analyzed enzalutamide and abiraterone resistant prostate cancer cells and found ubiquitin mediated proteolysis pathway was suppressed, and E3 ubiquitin ligases STUB1 is downregulated in enzalutamide and abiraterone resistant prostate cancer cells. STUB1 binds to AR-V7, degrades AR-V7 expression and suppresses its activity. HSP70, the STUB1 binding protein, also binds to AR-V7 and enhances AR-V7 transcriptional activity. Mechanistically, STUB1 disassociates HSP70 from AR-V7 binding and increases AR-V7 degradation. Targeting HSP70 by siRNA or small molecular inhibitors (Apoptozole and Ver155008) significantly suppressed prostate cancer growth and improved enzalutamide and abiraterone treatment through AR-V7 inhibition in vitro and in vivo. Additionally, HSP70 expression is upregulated in mCRPC tumors and correlates with AR-V7 levels in high Gleason score and metastatic prostate tumor specimens. CONCLUSION: Enzalutamide and abiraterone treatment induces the imbalance of AR-V7 proteostasis through the ubiquitin-proteolysis alteration. STUB1/HSP70 complex controls AR and AR variants proteostasis. Targeting HSP70 could be a valuable strategy to overcome the next generation anti-androgen resistance and improve their therapy. Citation Format: Chengfei Liu, Wei Lou, Joy C. Yang, Liangren Liu, Cameron M. Armstrong, Alan P. Lombard, Ruining Zhao, Onika DV Noel, Clifford G. Tepper, Hong-Wu Chen, Marc Dall’Era, Marc Dall’Era, Christopher P. Evans, Allen C. Gao. Proteostasis by HSP70/STUB1 complex regulates androgen receptor variants expression and confers resistance to enzalutamide and abiraterone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 334.

MP22-08 PROTEOSTASIS BY HSP70/STUB1 COMPLEX REGULATES ANDROGEN RECEPTOR VARIANTS EXPRESSION AND CONFERS RESISTANCE TO ENZALUTAMIDE AND ABIRATERONE

INTRODUCTION AND OBJECTIVES:Proteostasis is a complementary process by which cells control the protein biosynthesis, folding, trafficking and degradation. Evidence suggests that proteomic instability, such as protein misfolding and aggregation plays pivotal roles in cancer cell survival and progression. AR-V7 lacking the ligand binding domain confers resistance to enzalutamide and abiraterone in prostate cancer, targeting AR-V7 is an logical strategy to overcome the resistance. However, the mechanisms of AR-V7 proteostasis have not been fully studied so far. The objectives of this project are to investigate the roles of proteostasis in regulating AR-V7 expression and sensitivity to enzalutamide and abiraterone treatment.METHODS:Expression of HSP70 and STUB1 was determined by qRT-PCR and western blot. Expression of HSP70 and STUB1 was downregulated using specific siRNA. HSP70/STUB1 and AR-V7 interaction was determined by co-immunoprecipitation and dual immunofluorescence. The gene regulating mechanisms und...

Outcome, costs and dollar value of docetaxel and abiraterone in prostate cancer.

155 Background: Questions have emerged on the role of diet, cost and value of Abiraterone (Abi) in prostate cancer. Abi improved the quality of life (QoL), in contrast to docetaxel (Doc) used &gt; 6 cycles. We analyzed the data of 5 major clinical studies. Our objective was to weigh outcome, costs and dollar value of Abi and Doc in prostate cancer. Methods: Hazard ratios (HR) and company-posted prices were quoted. In hormone sensitive (HS), Doc costs x 6 cycles and Abi x 18-24 months were compared. Tests, follow-up and adverse events treatment costs (AEsTC) were computed separately. The probability of survival (PoS) was calculated as (1.0-HR) and dollar value as cost/PoS. Results: Doc costs x 6 cycles were $27,408 and AEsTC $1,450. In HS, at HR of 0.61 (Sweeney, 2015) and 0.73 (updated CHAARTED), Doc dollar value was $70,277 and $101,511 respectively. Abi costs x 2-years were $250,704, AEsTC $2,010, HR 0.73 (STAMPEDE) and value $928,533. In high risk HS (LATTITUDE), HR was 0.62 and value $659,747. At 18 months, Abi costs were $188,028. At an average HR of 0.73, value was $696,400. In comparison, in castrate-resistant (CR) chemo-naïve patients, Doc costs x 12 cycles were $54,816, AEsTC $4,840, HR 0.76 (Tannock, 2004) and value $228,400. Abi costs x one-year were $125,352 and AEsTC $1,050, HR 0.80 (COU-AA-302) and value $626,760. Conclusions: In HS, the results tend to suggest superior dollar value of Doc over Abi. In CR, the negative impact of Doc on QoL would undermine its dollar value.

Inhibition of autophagy significantly increases the antitumor effect of Abiraterone in prostate cancer.

Abiraterone acetate (AA) plus prednisone is an approved treatment of advanced prostate cancer (PCa). Autophagy is linked to drug resistance in numerous types of cancers. We hypothesized, that upregulation of autophagy is one of the mechanisms by which PCa cells survive AA anti-tumor treatment and therefore evaluated the potential effect of a combination with autophagy inhibition. Human PCa LNCaP cell lines were cultured in steroid-free medium and treated with AA. Autophagy was inhibited by 3-methyladenine, chloroquine and ATG5 siRNA knock-down. Cell viability and apoptosis was assessed by flow cytometry and fluorescence microscopy, and autophagy was monitored by immunohistochemistry, AUTOdot and Western blotting. Western blot revealed upregulation of ATG5 and LC3 II with a reduction of p62 protein expression in AA-treated cells, indicating upregulation of autophagy. These data were supported by results obtained with immunocytochemistry and AUTOdot assays. Using flow cytometry, we showed that combining AA with autophagy inhibition significantly impaired cell viability (1.3-1.6-fold, p < 0.001) and increased apoptosis (1.4-1.5-fold, p < 0.001) compared to AA treatment alone. AA activates autophagy as a cytoprotective mechanism in LNCaP prostate cancer cells and targeting of autophagy enhances the antitumor effect of the compound.

Combination of selective polo-like kinase 1 (PLK1) inhibitor PCM-075 with abiraterone in prostate cancer and non-androgen-driven cancer models.

369 Background: The majority of metastatic castration-resistant prostate cancer (mCRPC) patients will become resistant to abiraterone. Drug combinations with abiraterone offer the possibility to extend patient benefit to anti-androgen therapy. PLK1, an essential mitotic kinase for onset of G2/M transition and cytokinesis, is over-expressed in prostate cancer, correlated positively with Gleason grade and PLK1 RNAi induces G2/M arrest and apoptosis in prostate cancer cells. PCM-075 (formerly NMS-1286937) is a potent, highly selective PLK1 inhibitor currently in clinical trials for the treatment of acute myeloid leukemia. Combination of PCM-075 with abiraterone was examined in mCRPC models and other cancer types for synergistic interaction. Methods: We used a variety of tumor cell lines (C4-2, LNCaP, BT-20, AU565, SK-OV-3), animal and computational modeling techniques to elucidate the mechanism and assess the potential clinical utility of synergistic tumor cell killing by PLK1 inhibitors (PLK1i), including PCM-075, with abiraterone. Results: Synergy was observed between abiraterone and PLK1i, including PCM-075, in models of CRPC (C4-2). In addition, PLK1i and abiraterone were synergistic in murine C4-2 xenografts. Unexpectedly, PLK1i sensitized a subset of non-prostate cancer cells to abiraterone, including AR-negative breast and ovarian cancer cells. In contrast to PLK1i, other mitotic arrest agents do not synergize with abiraterone. To elucidate the molecular basis this synergy, we screened a panel of cell lines and implemented a new computational method that links RNA expression patterns to drug combination synergy. This analysis implicated signaling through the retinoic acid (RA) nuclear receptors as a component of this synergy, which was validated experimentally. Increased basal expression of genes involved in RA metabolism in cancer cells is associated with increased synergy. Conclusions: Abiraterone has AR-independent effects that provide a mechanism and biomarkers predictive for synergistic killing when combined with the PLK1i PCM-075. This combination has potential to extend mCRPC patient benefit to abiraterone regardless of AR status.

Re: Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy

Re: Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy

VP08 Description Of A Strategy To Face Judicialization Of The Right To Heal

Introduction:The Ministry of Health in Uruguay has a health technology assessment division that provides decision makers with evidence-based information on the efficacy, safety, and costs of health technologies to be included in the Comprehensive Plan of Health Care. Since 2010, patients have begun to demand access to unfunded, high-cost technologies through writs of protection. Judicialization of the right to health increased rapidly from 2010 to 2014. In this context, a Technical Advisory Commission was created in 2015 to assess patient requests on a case-by-case basis. The purpose of this study was to evaluate the results obtained with a new strategy developed to face the judicialization of access to high-cost technologies.Methods:The methodology used to evaluate the implementation of the strategy consisted of reviewing a database of access requests from October 2016 to October 2017. The demographic characteristics, technologies requested, prescriptions, and results of the process were analyzed.Results:In the study period 654 technologies were requested for funding through the process. The included population had a mean age of 60 years; sixty-two percent were men. Of the technologies requested, eighty-five percent were drugs and fifteen percent were devices. The requested technologies included cancer treatments (thirty-five percent) or drugs and devices for the treatment of rheumatologic, ophthalmologic, infectious, neurologic, and cardiovascular conditions. The six most requested technologies (forty-five percent of all requests) were: abiraterone for prostate cancer; aortic endoprosthesis for vascular aneurysm; lenalidomide, rituximab, and azacitidine for oncohematologic diseases; and cetuximab for colorectal cancer. The Ministry of Health funded thirty-six percent of the requests.Conclusions:The new strategy was successful in reducing the judicialization of access to unfunded, high-cost technologies in Uruguay, and it helped to prioritize the inclusion of new drugs in the national formulary.

Expanding the use of abiraterone in prostate cancer: Is earlier always better?

Androgen deprivation therapy (ADT), the inhibition of testosterone production via orchiectomy or the administration of a luteinizing hormone-releasing hormone (LHRH) agonist (e.g. leuprolide, goser...

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy

BackgroundAbiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design.MethodsWe randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer).ResultsA total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events).ConclusionsAmong men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476, and Current Controlled Trials number, ISRCTN78818544.)