Cost-Effectiveness Analysis of Abiraterone Acetate Treatment Compared With Cabacitaxel in Costa Rica, in Patients with Metastatic Castration-Resistant Prostate Cancer That Have Failed to Chemotherapy with Docetaxel
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To assess the cost-effectiveness of Abiraterone Acetate plus Prednisone (A-P) compared with Cabazitaxel plus Prednisone (C-P) in Costa Rica, in patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) that have failed to chemotherapy with Docetaxel. A three-health state cohort simulation Markov Model (progression-free, post-progression and death) was developed based on overall and progression free survival data. The time frame was 10 years. The perspective was that of the Public System of Health of Costa Rica. The health outcomes of interest were Quality Adjusted Life Years (QALYs) and Life Years (LYs). Efficacy data was taken from clinical trials (COU-AA-301 for A-P and TROPIC for C-P). Utilities for health states and negative utilities for adverse events were estimated based on quality of life endpoints of the COU-AA-301 trial. The base year was 2012. All costs are presented in Costa Rican currency (Colones - CRC). Costs and outcomes were discounted at 5%. Probabilistic sensitivity (PSA) analysis was performed to evaluate uncertainty surrounding the parameters. A-P resulted in 0.79 QALYs and 1.35 LYs, per patient, respectively. C-P resulted in 0.71 QALYs and 1.28 LYs, per patient, respectively. Mean total costs per patient were: CRC 33.881.184 for A-P and CRC 41.981.207 for C-P. The results of the probabilistic sensitivity analysis showed that, when compared with C-Z, A-P was found dominant (associated with reduced costs and increased QALYs) in the majority of the iterations. A-P had an 89% probability of being cost effective, independent of the willingness to pay, when compared to C-P. A-P can be considered dominant (cost-saving), when compared with C-P, in patients with Metastatic Castration-Resistant Prostate Cancer that have failed to chemotherapy with Docetaxel, from the perspective of the Public System of Health of Costa Rica.Keywords:
Abiraterone acetate
Cabazitaxel
Abstract Background: Cabazitaxel (Jevtana®), a novel semi-synthetic taxane derived from 10-deacetyl baccatin III, was recently approved by the FDA and EMA for patients with metastatic hormone-refractory prostate cancer previously treated with docetaxel-based therapy. Cabazitaxel, which stabilizes in vitro microtubules as efficiently as docetaxel, was selected for clinical development for several reasons including: better anti-proliferative activity than docetaxel against chemotherapy resistant tumor cell lines (Bissery MC, AACR 2000), broad spectrum of in vivo anti-tumor activity docetaxel-sensitive tumors, and activity in tumor models in which docetaxel was either poorly active or inactive (Vrignaud P, AACR 2000). Interestingly, unlike docetaxel, cabazitaxel is able to cross the blood-brian barrier (Dykes DJ, AACR 2000) and has demonstrated activity in intracranial human glioblastomas. Further, in preclinical studies the combination of cabazitaxel and cisplatin exhibit therapeutic synergism (Vrignaud P, AACR 2011). Methods: In order to explore other therapeutic indications, the anti-tumor activity of cabazitaxel was evaluated in comparison to docetaxel in 3 different xenograft models of human pediatric tumors: RH-30 (rhabdomyosarcoma), TC-71 and SK-ES-1 (Ewing's tumors) in SCID female mice. Cabazitaxel and docetaxel were administered as single agents, IV in a dose response study (14.5, 9.0, 5.6 & 3.5 mg/kg), 5 days apart (e.g., days 14 and 18) after SC tumor implantation. Results: In the rhabdomysarcoma RH-30 model, cabazitaxel achieved 100% complete regression (CR) at the 2 highest dose levels and tumor regressions were also observed at the third dose level. Tumor free survivors (TFS on day 120) were observed only in the cabazitaxel treatment groups, 14.5 mg/kg (6/6) and at 9 mg/kg (5/6). In comparison, docetaxel induced CR only at the highest dose-level (14.5 mg/kg) tested. Against TC-71, cabazitaxel achieved 6/7 TFS at14.5 mg/kg and 9 mg/kg and 6/7 partial regressions (PR) were observed at 5.6 mg/kg. However, docetaxel only induced CR at the highest dose-level tested (14.5 mg/kg) with 1/7 TFS at day 120. Against SK-ES-1, cabazitaxel achieved 100% PR at 14.5, 9.0, 5.6 mg/kg, with 6/7 CR, leading to 3/7 TFS at the highest doses tested. In comparison, docetaxel induced 3/7 CR at the highest dose tested and no TFS were observed. Conclusion: Both cabazitaxel and docetaxel showed significant antitumor activity in all 3 human pediatric tumor xenografts; however, cabazitaxel demonstrated greater activity than docetaxel at comparable dose levels. Taken together, preclinical data with cabazitaxel including activity in brain tumors and therapeutic synergism with cisplatin, support its development in pediatric indications. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2775. doi:1538-7445.AM2012-2775
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Abstract Background: Cabazitaxel (Jevtana®), a semi-synthetic taxane, was approved for patients with metastatic hormone-refractory prostate cancer previously treated with docetaxel-based therapy. Cabazitaxel, which stabilizes microtubules as efficiently as docetaxel, has a better antiproliferative activity than docetaxel against chemotherapy resistant tumor cell lines, a broad spectrum of in vivo antitumor activity in docetaxel-sensitive tumors and in tumor models in which docetaxel was either poorly active or inactive. Unlike docetaxel, cabazitaxel is able to cross the blood-brain barrier and is active in intracranial human glioblastomas (AACR 2000). The preclinical combination of cabazitaxel and cisplatin exhibits therapeutic synergism (AACR 2011). Finally, cabazitaxel demonstrates greater activity than docetaxel in 3 pediatric tumor xenografts, 1 rhabdomyosarcoma and 2 Ewing's sarcomas (AACR 2012). Methods: The anti-tumor activity of cabazitaxel was further evaluated in comparison to docetaxel in 3 pediatric patient-derived tumor xenografts (PDX): 2 osteosarcomas derived from lung metastases of a 19 year old male (DM77) and a 3 year old female (DM113) patient; 1 Ewing's sarcoma taken from the bone of a 17 year old male patient (DM101). Cabazitaxel and docetaxel were dosed IV at 5.8, 9.3, 15 or 24.2 mg/kg, every 4 days for a total of 3 doses (initial tumor burden = 125 - 250 mm3). Results: Both cabazitaxel and docetaxel demonstrated antitumor activity in these 3 PDX. In DM113, cabazitaxel is significantly more active than docetaxel at 9.3, 15 and 24.2 mg/kg. Additionally, when comparing the numbers of partial regressions (PR ≥ 50 % initial tumor size for at least 7days), cabazitaxel is more potent than docetaxel at 15 (4/10 PR versus 0/10 PR, respectively) and at 24.2 mg/kg (5/10 PR versus 1/10 PR, respectively). Using body weight loss as a gross indicator of toxicity, docetaxel appears to more toxic than cabazitaxel in the 2 other PDX studies. In DM101, cabazitaxel at 15 or 24.2 mg/kg doses was significantly more active than docetaxel at the same dose or at the equitoxic dose (9.3 or 15 mg/kg, respectively). In addition, cabazitaxel induces more complete regressions (CR = no palpable tumors for at least 7days) and tumor free animals on day 60 (TF) than docetaxel (9/9 CR and 7/9 TF for cabazitaxel versus 4/9 CR and 1/9 TF for docetaxel at 15 mg/kg; 9/9 CR and 8/9 TF for cabazitaxel versus 3/9 CR and 2/9 TFS for docetaxel at 24.2 mg/kg). Finally, in DM77, cabazitaxel at 15 and 9.3 mg/kg is also more active than docetaxel at an equivalent dose or a toxicity adjusted dose (9.3 or 5.8 mg/kg, respectively). Conclusion: Both cabazitaxel and docetaxel are active in these 3 human pediatric PDX; however, cabazitaxel demonstrates greater activity than docetaxel. Taken together, preclinical data with cabazitaxel including activity in brain tumors and therapeutic synergism with cisplatin, support its development in pediatric indications. Citation Format: Patricia Vrignaud. Antitumor activity of cabazitaxel in pediatric patient-derived tumor xenografts (PDX). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5508. doi:10.1158/1538-7445.AM2013-5508
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Docetaxel is the standard first-line chemotherapy for men with metastatic castration-resistant prostate cancer. Until recently, there was no standard therapy after failure of docetaxel treatment. Cabazitaxel has been shown to improve overall survival in this setting. As a result, the treatment paradigm for mCRPC is changing rapidly. The improved survival shown with cabazitaxel provides an important new opportunity to treat men with mCRPC after docetaxel treatment. Despite the toxicity recorded in the pivotal study, subsequent trials have shown that cabazitaxel is a safe drug. Patient selection and the optimal interval between prior docetaxel treatment and cabazitaxel remain the critical issues. According to a subanalysis of the various studies discussed in this review, there is a patient profile that will probably benefit from use of cabazitaxel after docetaxel failure. Cabazitaxel represents a new treatment option for patients with prostate cancer.
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The correlation of the oncological outcomes of docetaxel and cabazitaxel in Japanese metastatic castration-resistant prostate cancer (mCRPC) patients has not been unclear. This study included a total of 47 consecutive Japanese mCRPC patients treated with cabazitaxel and assessed the prognostic significance of cabazitaxel, focusing on patient age and the correlation of efficacy between docetaxel and cabazitaxel. Prostate-specific antigen (PSA) decline was observed in 27 patients (57.4%), including 19 (40.0%) achieving the response defined by PSA decline ≥ 30%. The median overall survival (OS) periods after the introduction of cabazitaxel was 16.1 months. Twenty (42.6%) were judged to have responded to cabazitaxel with a PSA decrease ≥ 30% from the baseline. A 30% PSA response to cabazitaxel was achieved in 4 (50.0%) patients with ≧ 75 years (n = 8) and 16 (41.0%) patients with less than 75 years (n = 39). There was no significant correlation between the PSA response and patients’ age (p = 0.707). A 30% PSA response to cabazitaxel was achieved in 13 (46.4%) and 7 (36.8%) patients with and without that to docetaxel, respectively. A 30% PSA response to cabazitaxel was achieved in 5 (16.6%) and 7 (41.2%) patients who had treated with less than 10 cycles docetaxel or 10 ≦ cycles, respectively. Univariate and multivariate analyses revealed that there were no significant correlation of patient age (p = 0.537), the response to prior docetaxel therapy (p = 0.339) or cycles of docetaxel therapy (p = 0.379) with shorter OS. These results indicate that the introduction of cabazitaxel for Japanese mCRPC patients could result in oncological outcomes without any association with patient’s age and the profiles of previous docetaxel therapy.
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Chemotherapy agents for patients with metastatic castration-resistant prostate cancer (mCRPC) include docetaxel and cabazitaxel. Although docetaxel is approved in the first-line treatment setting, a few studies have shown that selected patients can benefit from docetaxel rechallenge.We, here, report the case of a heavily pretreated mCRPC patient who reported clinical benefit from receiving docetaxel after previous exposure to docetaxel, cabazitaxel, abiraterone, and enzalutamide.After 4 cycles of treatment, patient's performance status had improved to 1, the hemoglobin level was 12.9 g/dL and his serum prostate specific antigen levels were reduced by >70%, with no treatment-related adverse events.Although docetaxel rechallenge is a therapeutic option for selected patients, the risk of cumulative toxicity described in literature must be carefully considered.As the risk of cabazitaxel-related cumulative toxicity is probably lower, retreatment with cabazitaxel rather than docetaxel may also be an option in the setting of heavily pretreated mCRPC patients.
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Resistance to docetaxel is common in metastatic castration-resistant prostate cancer (mCRPC) and may be caused by sub-therapeutic intratumoral drug concentrations. Cabazitaxel demonstrated survival benefit in docetaxel-pretreated and docetaxel-refractory patients. In this study, we investigated whether the superior antitumor activity of cabazitaxel in mCRPC is explained by higher intratumoral cabazitaxel levels. Since recent studies suggest a reduced efficacy of docetaxel following treatment with novel androgen receptor (AR)-targeted agents, we also investigated taxane efficacy in an enzalutamide-resistant tumor model.Intratumoral concentrations of docetaxel and cabazitaxel were correlated with antitumor activity in docetaxel-naïve, docetaxel-resistant, and enzalutamide-resistant patient-derived xenografts (PDXs) of prostate cancer.Intratumoral drug levels were negatively related to intrinsic and acquired resistance to docetaxel. Also, the observed stronger antitumor activity of cabazitaxel was associated with increased cumulative exposure and higher intratumoral of cabazitaxel concentrations in all PDXs.The superior antitumor activity of cabazitaxel in docetaxel- and enzalutamide-resistant tumors can be partly attributed to higher intratumoral drug concentrations. Especially for patients who are intrinsically resistant to docetaxel resulting from suboptimal intratumoral docetaxel concentrations, cabazitaxel may be the preferred chemotherapeutic agent. Prostate 76:927-936, 2016. © 2016 Wiley Periodicals, Inc.
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<div>Abstract<p>Cabazitaxel, a novel chemotherapeutic taxane, is effective against docetaxel-resistant cells and tumors. It is approved for treatment of metastatic hormone-refractory prostate cancer in patients pretreated with docetaxel. Objective responses have been observed in many other cancers, including pretreated metastatic breast cancer. Cabazitaxel and docetaxel share a high degree of structural similarity. The basis for cabazitaxel's efficacy is unclear, and its mechanism has not been described. We compared the effects of cabazitaxel and docetaxel on MCF7 human breast cancer cells expressing fluorescent tubulin. Both drugs inhibited cell proliferation (IC<sub>50s</sub>, cabazitaxel, 0.4 ± 0.1 nmol/L, docetaxel, 2.5 ± 0.5 nmol/L) and arrested cells in metaphase by inducing mitotic spindle abnormalities. Drug concentrations required for half-maximal mitotic arrest at 24 hours were similar (1.9 nmol/L cabazitaxel and 2.2 nmol/L docetaxel). Cabazitaxel suppressed microtubule dynamic instability significantly more potently than docetaxel. In particular, cabazitaxel (2 nmol/L) suppressed the microtubule shortening rate by 59% (compared with 49% for 2 nmol/L docetaxel), the growing rate by 33% (vs. 19%), and overall dynamicity by 83% (vs. 64%). Cabazitaxel was taken up into cells significantly faster than docetaxel, attaining an intracellular concentration of 25 μmol/L within 1 hour, compared with 10 hours for docetaxel. Importantly, after washing, the intracellular cabazitaxel concentration remained high, whereas the docetaxel concentration was significantly reduced. The data indicate that the potency of cabazitaxel in docetaxel-resistant tumors is due to stronger suppression of microtubule dynamics, faster drug uptake, and better intracellular retention than occurs with docetaxel. <i>Mol Cancer Ther; 13(8); 2092–103. ©2014 AACR</i>.</p></div>
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Abstract Introduction: Cabazitaxel (C) is a novel taxane active in preclinical models of both chemotherapy-sensitive and -resistant human tumors. Cabazitaxel is active in patients with advanced prostate cancer who have progressed following docetaxel (D) treatment. We compared the antitumor activity of cabazitaxel with that of docetaxel (both provided by Sanofi) against in vitro and in vivo models of pediatric cancers. Methods: Both agents were evaluated against the 23 cell lines of the PPTP in vitro panel using 96 hour exposure at concentrations from 0.01 nM to 0.1 μM. They were tested against the PPTP solid tumor xenografts (SCID mice) using a dose of 7.5 or 10.0 mg/kg administered by the IV route every 4 days X 3. Results: In vitro the median relative IC50 (rIC50) for cabazitaxel was 0.47 nM and for docetaxel was 0.88 nM. Cabazitaxel and docetaxel rIC50 and Ymin% values were significantly correlated with each other. Cabazitaxel rIC50 values were significantly correlated with cell line ABCB1 expression, but showed a weaker relationship compared to that for docetaxel. In vivo, there was a trend for greater weight loss and greater toxicity for cabazitaxel-treated versus docetaxel-treated animals. A direct comparison of the EFS distributions for cabazitaxel and docetaxel showed that 5 xenografts had significantly longer EFS for cabazitaxel compared to docetaxel, while docetaxel was more effective for no models for this measure. 5 of 10 xenografts showed maintained complete responses (MCRs) to cabazitaxel, with MCRs observed across multiple histologies. Only 1 of 10 docetaxel-treated models showed an MCR. In vivo results are summarized in the Table using standard PPTP objective response criteria. Tumor Histology C Response D Response P-value for EFS (C vs D) KT-10 Wilms MCR PD2 <0.001 SK-NEP-1 Ewing sarcoma MCR MCR 0.211 CHLA258 Ewing sarcoma MCR PR 0.033 Rh30R Rhabdomyosarcoma SD PD2 <0.001 Rh18 Rhabdomyosarcoma PD2 PD1 0.147 Rh36 Rhabdomyosarcoma MCR PD2 0.033 NB-1691 Neuroblastoma PD2 PD1 <0.001 OS-1 Osteosarcoma SD PD2 1.000 OS-17 Osteosarcoma SD CR 0.195 OS-33 Osteosarcoma MCR CR 0.552 Conclusions: Cabazitaxel was more potent in vitro than docetaxel against the PPTP cell lines and showed greater in vivo activity than docetaxel, although with somewhat greater toxicity. (Supported by award NO1-CM-42216 from the NCI). Citation Format: Peter J. Houghton, Min Kang, C Patrick Reynolds, Richard B. Lock, Hernan Carol, Richard Gorlick, E Anders Kolb, John M. Maris, Stephen T. Keir, Catherine A. Billups, Raushan T. Kurmasheva, Malcolm Anders Smith. Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of the antimicrotubule agents cabazitaxel and docetaxel. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2754. doi:10.1158/1538-7445.AM2013-2754
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