Abiraterone Acetate Treatment Research Articles

ARTO trial (NCT03449719), a randomized phase II trial enrolling oligometastatic castration-resistant prostate cancer patients treated with first-line abiraterone acetate with or without stereotactic body radiation therapy: Preliminary results comprehensive of biochemical outcomes and circulating tumor cells analysis.

118 Background: Androgen Receptor Targeted Agents (ARTA) represent one of the main treatment options for metastatic castrate resistant prostate cancer (mCRPC). Addition of stereotactic radiation therapy (SBRT) to ablate metastatic foci may improve clinical outcomes in oligometastatic setting. ARTO trial (NCT03449719) is a randomized phase II trial testing the benefit of upfront SBRT on all sites of metastatic disease in oligo-mCRPC patients undergoing I line therapy with Abiraterone Acetate (AA). In this preliminary analysis, we report results after 6 months of follow up, together with an exploratory analysis of androgen receptor splice variants (ARV7/ARFL) Prostate Specific Antigen (PSA) and Prostate Specific Membrane Antigen (PSMA) expression on Circulating Tumor Cells (CTCs) detected in this cohort of patients. Methods: 31 patients affected by oligo-mCRPC (defined as < 3 non-visceral metastatic lesions) were randomized to receive I line AA therapy with or without SBRT on all metastatic sites. Baseline blood samples to detect CTCs and evaluate their ARV7, ARFL, PSA and PSMA expression were taken before AA treatment start. Assessments comprehensive of clinical examination and serum PSA were performed every three months. Toxicity was assessed by the Common Terminology Criteria for Adverse Events toxicity scale (CTCAE v.4.03). Results: Thirteen and 18 patients were enrolled in the treatment and control arm, respectively. Nineteen metastatic lesions were treated with SBRT in the treatment arm. At 6 months, complete response (defined as a serum PSA level < 0.2 ng/dl) and biochemical response (defined as a PSA reduction > 50% if compared to baseline) were achieved in 6 vs 4 and in 10 vs 8 patients in the treatment vs control arm, respectively. One patient in the treatment arm died for other causes, 1 biochemical progression occurred in the control arm. No adverse events occurred in both arms of treatment. CTCs analysis was available for 10 patients, out of whom 4 were found positive for CTCs (1 and 3 from the treatment and control arm, respectively). ARV7 and ARFL were expressed in 1 patient from the control arm, PSMA was expressed in all CTC positive patients, PSA was expressed in 2 patients from the control and one from the treatment arm. Conclusions: SBRT+AA in oligo-mCRPC patients was safe and yielded promising biochemical results. CTCs detection in this selected cohort of oligo-mCRPC was lower if compared to historical data of unselected mCRPC patients. Data about ARV7, ARFL, PSA and PSMA expression represent an interesting snapshot of biomarker arrangement in this setting. Clinical trial information: NCT03449719.

Abiraterone Acetate Induces CREB1 Phosphorylation and Enhances the Function of the CBP-p300 Complex, Leading to Resistance in Prostate Cancer Cells.

Abiraterone acetate (AA), an inhibitor of cytochrome P450 17alpha-hydroxylase/17, 20 lyase, is an FDA-approved drug for advanced prostate cancer. However, not all patients respond to AA, and AA resistance ultimately develops in patients who initially respond. We aimed to identify AA resistance mechanisms in prostate cancer cells. We established several AA-resistant cell lines and performed a comprehensive study on mechanisms involved in AA resistance development. RNA sequencing and phospho-kinase array screenings were performed to discover that the cAMP-response element CRE binding protein 1 (CREB1) was a critical molecule in AA resistance development. The drug-resistant cell lines are phenotypically stable without drug selection, and exhibit permanent global gene expression changes. The phosphorylated CREB1 (pCREB1) is increased in AA-resistant cell lines and is critical in controlling global gene expression. Upregulation of pCREB1 desensitized prostate cancer cells to AA, while blocking CREB1 phosphorylation resensitized AA-resistant cells to AA. AA treatment increases intracellular cyclic AMP (cAMP) levels, induces kinases activity, and leads to the phosphorylation of CREB1, which may subsequently augment the essential role of the CBP/p300 complex in AA-resistant cells because AA-resistant cells exhibit a relatively higher sensitivity to CBP/p300 inhibitors. Further pharmacokinetics studies demonstrated that AA significantly synergizes with CBP/p300 inhibitors in limiting the growth of prostate cancer cells. Our studies suggest that AA treatment upregulates pCREB1, which enhances CBP/p300 activity, leading to global gene expression alterations, subsequently resulting in drug resistance development. Combining AA with therapies targeting resistance mechanisms may provide a more effective treatment strategy.

Effects of abiraterone acetate plus prednisone on bone turnover markers in chemotherapy-naïve mCRPC patients after ADT failure: A prospective analysis of the italian real-world study ABITUDE

BackgroundBone remodeling is disrupted in metastatic disease, which affects > 70% of metastatic castration-resistant prostate cancer (mCRPC) patients. As a result, abnormal levels of specific bone turnover biomarkers (BTMs) are released. In this prospective ancillary analysis of the Italian real-world study ABITUDE, four markers were measured during abiraterone acetate plus prednisone (AAP) treatment in chemotherapy-naïve mCRPC men failing androgen-deprivation therapy. MethodsPatients were enrolled if a blood sample was obtained before the first administration of abiraterone (baseline); ad-hoc blood samples were withdrawn during routine tests after 3, 6, and 12 months. A centralized lab measured bone alkaline phosphatase (BALP, osteoblast activity marker), type-I collagen-C-telopeptide (CTX-1, bone resorption marker), parathyroid hormone (PTH) and vitamin D (vitD). At each time point, intra-patient variations vs baseline were compared by the signed-rank test (statistical significance: P-value < 0.05). ResultsOf 481 patients enrolled in ABITUDE, 186 (median age: 76 [range: 53–93] years) met the substudy criteria: 74.7% had bone metastases, 11.8% were on bone-targeted therapies (BTT) and 14.0% on vitD supplementation. BALP decreased significantly at month 6 (P = 0.0010) and 12 (P < 0.0001) and CTX-1 at month 6 (P = 0.0028); PTH increased at month 3 (P < 0.0001); no significant difference in vitD levels was observed. Similar findings were observed in BTT-untreated patients. The reduction in BALP and CTX-1 levels was more pronounced in patients with than without bone metastases; in the latter group, no significant variation in BALP and CTX-1 levels was observed. ConclusionsAAP seems to exert an effect on the microenvironment of metastatic but not of normal bone, which likely contributes to its antitumoral activity.

A high neutrophil-to-lymphocyte ratio is a poor prognostic factor for castration-resistant prostate cancer patients who undergo abiraterone acetate or enzalutamide treatment

BackgroundInflammatory cytokine markers, including the neutrophil-to-lymphocyte ratio (NLR), monocyte-lymphocyte ratio, and platelet-to-lymphocyte ratio, play important roles as prognostic markers in several solid malignancies, including prostate cancer. We previously reported the NLR as a poor prognostic marker in bladder cancer, upper-urothelial carcinoma, adrenocortical carcinoma, penile cancer, and prostate cancer. This study examined the importance of the NLR as a prognostic marker for castration-resistant prostate cancer (CRPC) patients who received abiraterone acetate or enzalutamide.MethodsA total of 805 prostate cancer patients developed in CRPC status were enrolled in this study. Of these patients, 449 received abiraterone acetate (ABI; 188 cases) or enzalutamide (ENZ; 261 cases) treatment, and the pre-treatment NLR values of these patients were obtained. We investigated the prognosis in those with higher and lower NLR values.ResultsThe median NLR was 2.90, and a receiver operating characteristics analysis suggested a candidate cut-off point of 3.02. The median overall survival (OS) was 17.3 months in the higher NLR group (≥3.02) and 27.3 months in the lower NLR group (< 3.02) (p < 0.0001). This trend was also observed in both the ABI and ENZ groups (ABI: 29.3 vs. 15.1 months; ENZ: NR vs. 19.5 months; p < 0.0001 and < 0.0001, respectively). A multivariate analysis revealed that a higher NLR was an independent risk factor. The NLR value was thus shown to be correlated with the prostate cancer progression.ConclusionsA higher NLR was associated with a poorer OS for CRPC patients who received ABI or ENZ. The NLR was positively correlated with prostate cancer progression.

Cost-Effectiveness Assessment of Monitoring Abiraterone Levels in Metastatic Castration-Resistant Prostate Cancer Patients

ObjectivesAbiraterone acetate is registered for the treatment of metastatic castration-sensitive and resistant prostate cancer (mCRPC). Treatment outcome is associated with plasma trough concentrations (Cmin) of abiraterone. Patients with a plasma Cmin below the target of 8.4 ng/mL may benefit from treatment optimization by dose increase or concomitant intake with food. This study aims to investigate the cost-effectiveness of monitoring abiraterone Cmin in patients with mCRPC. MethodsA Markov model was built with health states progression-free survival, progressed disease, and death. The benefits of monitoring abiraterone Cmin followed by a dose increase or food intervention were modeled via a difference in the percentage of patients achieving adequate Cmin taking a healthcare payer perspective. Deterministic and probabilistic sensitivity analyses were performed to assess uncertainties and their impac to the incremental cost-effectiveness ratio (ICER). ResultsMonitoring abiraterone followed by a dose increase resulted in 0.149 incremental quality-adjusted life-years (QALYs) with €22 145 incremental costs and an ICER of €177 821/QALY. The food intervention assumed equal effects and estimated incremental costs of €7599, resulting in an ICER of €61 019/QALY. The likelihoods of therapeutic drug monitoring (TDM) with a dose increase or food intervention being cost-effective were 8.04%and 81.9%, respectively. ConclusionsMonitoring abiraterone followed by a dose increase is not cost-effective in patients with mCRPC from a healthcare payer perspective. Monitoring in combination with a food intervention is likely to be cost-effective. This cost-effectiveness assessment may assist decision making in future integration of abiraterone TDM followed by a food intervention into standard abiraterone acetate treatment practices of mCRPC patients.

Association Between CYP17A1, CYB5A Polymorphisms and Efficacy of Abiraterone Acetate/Prednisone Treatment in Castration-ResistantProstate Cancer Patients.

PurposeThe purpose of this study was to investigate the association between single nucleotide polymorphisms (SNPs) of CYP17A1, CYB5A and the efficacy of abiraterone acetate treatment in patients with castration-resistant prostate cancer (CRPC).Patients and MethodsData were collected from 58 CRPC patients who had been treated with abiraterone acetate/prednisone (AA/P). The SNPs rs743572 and rs10883783 on CYP17A1 and SNPs rs1790834 and rs1790858 on CYB5A were assayed, and their relationship with prostate-specific antigen (PSA) response in patients after AA/P treatment, overall survival (OS) and progression-free survival (PFS) were analyzed by logistic regression, Cox regression, Kaplan–Meier and Log rank analyses.ResultsThe SNP rs1790834 on CYB5A showed significant association with PSA response in CRPC patients treated with AA/P (P < 0.05), but rs743572, rs10883783 and rs1790858 did not. The rs1790834 variant significantly decreased both PFS and OS (P < 0.05).ConclusionThe CYB5A rs790834 genotype is a novel SNP related to CRPC and may be used as a biomarker for CRPC treatment.

Fracture risk and survival outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) sequentially treated with abiraterone acetate (AA) and radium-223 (RA223).

e17593 Background: The increased incidence of bone fractures found in pts who received the AA-RA223 combination compared to those treated with AA alone in the ERA223 trial led to restrictive recommendations by the European Medicines Agency which limited the use of RA223 to pts who have received at least two previous treatments for mCRPC or who cannot receive any other treatment. Moreover, clinicians started to debate the risk of RA223-related fractures associated with the sequential administration of AA and RA223. The aim of this retrospective study was to assess the safety of administering RA223 to pts who have progressed during AA treatment mainly in terms of the rate of skeletal fractures. Methods: We retrospectively reviewed the records of mCRPC pts who received RA223 after progressing during an AA treatment line in everyday clinical practice in ten Italian Hospitals. Results: We reviewed data of a consecutive series of 94 mCRPC pts. Most of the pts (85.1%) received RA223 as second- or third-line treatment and had a Soloway score 2 or 3 (90%). RA223 treatment was well-tolerated: there were only four cases of grade 3 anemia, two case of grade 3 leukopenia, and one case of grade 3 neutropenia. The overall fracture rate of 2.1%: one fracture was recorded during the course of RA223 treatment, and one was recorded one month after its end. The fractures both occurred at metastatic sites in pts who were not treated with antiresorptive agents. Median overall survival (OS) from RA223 start was more than 14 mos and the pts who received Ra223 in second line (which is not allowed today in Europe) had the same median OS as those who received this agent in later lines. Conclusions: The findings of this study showed that the treatment with RA223 as subsequent treatment line after AA was active and safe with a very low risk of a fracture. The OS outcomes indicated that the administration of RA223 in early treatment lines is not detrimental, even after AA. Thus the present observational report makes a valuable contribution to the current debate concerning the risks and benefits of including RA223 in the therapeutic algorithm.

Clinical outcomes of abiraterone acetate and predictors of its treatment duration in metastatic castration-resistant prostate cancer: Real-world experience in the Southeast Asian cohort.

It is of much interest to understand the efficacy of abiraterone acetate (AA) in routine clinical practice. We assessed the clinical outcome of AA in patients with metastatic castration‐resistant prostate cancer (mCRPC) and determined clinical factors associated with AA treatment duration in real‐world setting. This real‐world cohort consisted of 93 patients with mCRPC treated with AA in Thailand (58.1%) and Malaysia (41.9%). Primary endpoints were overall survival (OS) and biochemical progression‐free survival (bPFS). Secondary endpoints were predictors associated with AA treatment duration evaluated with Cox proportional hazards regression. Around 74% were chemotherapy‐naïve. The median AA treatment duration was 10 months (IQR 5.6‐17.1). Malaysians had a relatively lower median OS and bPFS (OS 17.8 months; 95% CI 6.4‐29.1, bPFS 10.4 months; 95% CI 8.8‐12.0) compared to Thais (OS 27.0 months; 95% CI 11.3‐42.7, bPFS 14.0 months; 95% CI 5.8‐22.2), although it did not achieve statistical significance (P > .05). Patients with longer AA treatment duration (>10 months) had lower risk of death and longer bPFS, compared to those with shorter AA treatment duration (≤10 months) (hazard ratio [HR] 0.10, 95% CI 0.05‐0.22 and HR 0.13, 95% CI 0.06‐0.25, respectively). Multivariable analysis showed that PSA at AA initiation, presence of PSA response and chemotherapy‐naive were independently associated with AA duration (P < .05). Abiraterone acetate is well‐tolerated in the Southeast Asian cohort with comparable survival benefits to other Asian populations in real‐world setting. Lower PSA levels at AA initiation, presence of PSA response, and chemotherapy‐naive were significant in determining AA treatment duration.

COVID-19: Risk of increase in smoking rates among England's 6 million smokers and relapse among England's 11 million ex-smokers.

Background/Aim: The main purpose of this study was to evaluate the outcome of patients with prostate-specific antigen (PSA) progression after abiraterone acetate (AA) treatment for metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods: Between 2012 and 2017, 83 patients with clinically-confirmed mCRPC previously treated with docetaxel with/without cabazitaxel followed by AA were included in this retrospective study. All patients received 1,000 mg AA with 5 or 10 mg prednisolone. Among them, 59 were eligible for this study based on PSA progression during the clinical course. Patients were divided into two groups, AA responders and AA non-responders according to previous PSA response to AA treatment. Overall survival and treatment response to subsequent therapy were analyzed. Results: The median overall survival of the 59 patients after AA-treated PSA progression was 12 (95% confidence interval(CI)=7.6-16.4) months and was longer in the AA-responding group compared to the non-responding group (25 vs. 8 months, p&lt;0.001). The survival time after PSA progression on AA was longer in the AA-responsive group despite not being statistically different (13 vs. 7 months, p=0.126). Patients with AA treatment who received subsequent therapies after PSA progression had better overall survival than those without (18 vs. 4 months, p=0.003). In addition, there was a trend for better chemotherapy response in AA non-responders than AA responders, 62.5% (5/8) vs. 12.5% (1/8) respectively. Conclusion: In our small retrospective patient experience, effective sequential treatments for patients with mCRPC provided overall survival benefit. Previous treatment response can act as a clinical predictor for subsequent treatment.

Fracture risk and survival outcomes in metastatic castration-resistant prostate cancer patients sequentially treated with abiraterone acetate and RADIUM-223.

To evaluate the fracture risk and survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) who received sequentially abiraterone acetate (AA) and radium 223 [223Ra]RaCl2 in the daily clinical practice. We retrospectively reviewed the records of mCRPC patients who received [223Ra]RaCl2 immediately after progressing during an AA treatment line in everyday clinical practice. We reviewed data of a consecutive series of 94 mCRPC patients. Most of the patients (85.1%) received [223Ra]RaCl2 as second- or third-line treatment. [223Ra]RaCl2 treatment was well-tolerated; there were only four cases of grade 3 anaemia, two cases of grade 3 leukopenia and one case of grade 3 neutropenia. The overall fracture rate is 2.1%; one fracture was recorded during the course of [223Ra]RaCl2 treatment, and one was recorded 1month after its end. The fractures both occurred at metastatic sites. Median OS from [223Ra]RaCl2 start was more than 14months regardless of the treatment line when [223Ra]RaCl2 was administered. The findings of this study show that the treatment with [223Ra]RaCl2 immediately after AA was active and safe with a very low risk of a fracture. Thus, the present observational report makes a valuable contribution to the current debate concerning the risks and benefits of including [223Ra]RaCl2 in the therapeutic algorithm.

Abiraterone acetate treatment lowers 11-oxygenated androgens.

The human adrenal is the dominant source of androgens in castration-resistant prostate cancer (CRPC) and classic 21-hydroxylase deficiency (21OHD). Abiraterone, derived from the prodrug abiraterone acetate (AA), inhibits the activity of cytochrome P450 17-hydroxylase/17,20-lyase (CYP17A1), the enzyme required for all androgen biosynthesis. AA treatment effectively lowers testosterone and androstenedione in 21OHD and CRPC patients. The 11-oxygenated androgens are major adrenal-derived androgens, yet little is known regarding the effects of AA administration on 11-oxygenated androgens. To test the hypothesis that AA therapy decreases 11-oxygenated androgens. Samples were obtained from 21OHD or CRPC participants in AA or AA plus prednisone (AAP)-treatment studies, respectively. We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the 11-oxygenated androgens, 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone, in plasma or serum samples from six 21OHD and six CRPC patients before and after treatment with AA or AAP, respectively. In CRPC patients, administration of AAP (1000 mg/day AA with prednisone and medical castration) lowered all four 11-oxygenated androgens to below the lower limits of quantitation (<0.1-0.3 nmol/L), equivalent to 64-94% reductions from baseline. In 21OHD patients, administration of AA (100-250 mg/day for 6 days) reduced all 11-oxygenated androgens by on average 56-77% from baseline. We conclude that AA and AAP therapies markedly reduce the production of the adrenal-derived 11-oxygenated androgens, both in patients with high (21OHD) or normal (CRPC) 11-oxygenated androgens at baseline, respectively. Reduction of 11-oxygenated androgens is an important aspect of AA and AAP pharmacology.

Phase III study of pembrolizumab (pembro) plus enzalutamide (enza) versus placebo plus enza for metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-641.

TPS258 Background: The mechanisms of action of pembro, a PD-1 inhibitor, and enza, an androgen receptor inhibitor, may be synergistic in the treatment of patients (pts) with mCRPC. The phase 1b/2 KEYNOTE-365 (NCT02861573) study showed antitumor activity with pembro + enza in pts with mCRPC pretreated with abiraterone acetate. A phase 2 study (NCT02312557) of enza-pretreated patients with mCRPC showed that some pts had a profound and durable anticancer response to pembro + enza. Methods: KEYNOTE-641 (NCT03834493) is a randomized, double-blind, phase 3 trial to evaluate efficacy and safety of pembro + enza versus placebo + enza in pts with mCRPC. An estimated 1200 patients will be randomly assigned 1:1 to receive enza 160 mg/day + pembro 200 mg IV Q3W or enza 160 mg/day + placebo. Treatment will be stratified by prior abiraterone acetate treatment (yes/no), metastases location (bone only/liver/other), and prior docetaxel treatment for metastatic hormone-sensitive prostate cancer (yes/no). Adults (≥18 years) with histologically or cytologically confirmed mCRPC who experienced biochemical or radiographic progression, ECOG PS 0/1, and adequate organ function are eligible. Pts will be required to provide tissue for biomarker analysis. Intolerance to or progression while receiving prior abiraterone acetate therapy is permitted, but not required. Prior chemotherapy for mCRPC, checkpoint inhibition, or any treatment with a second-generation androgen receptor inhibitor is prohibited. Responses will be assessed by CT/MRI and radionuclide bone imaging per PCWG3-modified RECIST v1.1 Q9W during the first year and Q12W thereafter. Treatment will continue until progression, unacceptable toxicity, or consent withdrawal, with up to 2 years of pembro/placebo. Dual primary end points are OS and rPFS by blinded independent central review. Secondary end points are time to subsequent anticancer therapy or death, ORR, DOR, PSA response rate, PSA undetectable rate, time to PSA progression, time to pain progression, time to soft tissue progression, time to symptomatic skeletal-related event, and safety. Accrual began July 28, 2019. Clinical trial information: NCT03834493.

The effect of abiraterone acetate treatment on CREB and the development of abiraterone acetate resistance in prostate cancer cells.

177 Background: The androgen receptor (AR) remains an essential target in castration resistant prostate cancer (CRPC). Abiraterone acetate (AA), an inhibitor of CYP17A1, is an FDA approved drug for metastatic CRPC. AA can also be converted to the more active metabolite 4-abiraterone in vivo, which blocks multiple steroidogenic enzymes and antagonizes AR. However, not all patients respond to AA and AA resistance ultimately develops in those patients who initially respond. Methods: We established several AA resistant prostate cancer cell lines and performed a comprehensive study of mechanisms involved in the development of AA resistance. The AA-resistant cell lines are phenotypically stable with aggressive invasive features. By RNA-seq and phospho-kinase array screening, we found that the cAMP response element-CRE binding protein 1 (CREB1) is activated in AA resistant cell lines. Results: Over-expression of the wild type CREB1 or treatment with Forskolin desensitizes the cellular response to AA, while over-expressing the mutated CREB1 (S133A, an essential kinase site) did not significantly affect cell sensitivity to AA. Blocking pCREB1 with the CREB inhibitor increased the sensitivity of AA resistant cell lines to AA. The activation of pCREB1 in AA resistant cell lines may potentially activate the CBP/p300 complex. Our data demonstrated that treatment with a low dose of AA strongly synergistic the efficacy of CBP/p300 inhibitors in prostate cancer cell lines. Taken together, we found that AA treatment activates CREB1 and pCREB1 may interact with the CBP/p300 complex, leading to global gene expression alterations, which subsequently result in the development of drug resistance. Conclusions: Our study indicates that AR-targeted treatment potentially fosters de novo genetic and epigenetic alterations associated with progression. A more effective AR-targeted treatment for CRPC may be developed by considering low doses of multiple targets involved in the development of resistance pathways.

A prognostic score for overall survival in patients treated with abiraterone in the pre- and post-chemotherapy setting.

Background: Therapy resistance remains a serious dilemma in metastatic castration-resistant prostate cancer (mCRPC) with primary or secondary resistance frequently occurring against any given therapy. Available prognostic models for Abiraterone Acetate (AA) are specifically designed for either pre- or post-chemotherapy settings and mostly based on trial datasets not necessarily reflecting real-life. Results: A score of 0–2 (low-risk) is associated with an OS-probability of 80.0% (95%CI: 71.3–90.6) and 50.5% (95%CI: 38.7–66.0) after 1 and 2 years while a score of 3–4 (high risk) is associated with an OS-probability of 35.3% (95%CI: 22.3–55.8) and 5.7% (95%CI: 1.5–21.8), respectively. The bootstrapping survival analysis of the scoring-system revealed a median c-index of 0.80 (IQR: 0.79–0.82). Material and Methods: We developed a scoring-system using four real-life parameters 117 mCRPC patients treated with AA either pre- or post-chemotherapy. These parameters were evaluated using COX regression analysis. The scoring-system consists of binary-categorized parameters; when any of these exceeds the given cut-off, one point is added up to a final score ranging between 0–4 points. The final score was stratified by a median threshold of 2 into low- and high-risk groups. We evaluated the discriminative ability of our scoring-system using concordance probability (C-index) and Kaplan–Meier-analysis and applied a 100-times bootstrap for survival analysis. Conclusions: Our study introduces a novel prognostic scoring-system for OS of real-life mCRPC patients receiving AA treatment irrespective of the line of therapy. The scoring-system is simple and can be easily utilized based on PSA and LDH values, neutrophil to lymphocyte ratio, and ECOG performance status.

Predictive factors for abiraterone withdrawal syndrome

Introduction and objectiveAbiraterone withdrawal syndrome (AWS) is characterized by a transient decrease in the PSA after abiraterone acetate (AA) treatment discontinuation in patients diagnosed with metastatic castration-resistant prostate cancer (mCRPC). The aim of our study is to identify the possible predictive factors of AWS at diagnosis. Materials and methodsWe performed a retrospective study of 70 patients treated with AA at the Institut Català d’Oncologia – L’Hospitalet between 2015 and 2017. ResultsEleven patients presented AWS. The mean age at diagnosis was 65.73 years and the mean age of presentation was 74.18 years. Patients were in the ninth treatment cycle. The median PSA was: 30.5ng/ml at diagnosis, 33.24ng/ml in the AWS, and 15.78ng/ml before starting another treatment. The median follow-up period after AWS was 8.2 months. The predictive factors of AWS would be: high PSA (p=0.002), ISUP≥4 (p=0.002) and stage IV at diagnosis (p<0.001). Patients with a T stage present high risk, but without statistical significance. An AUC of 0.84 was obtained, with a 95% CI between 0.77 and 0.92 (p<0.001). ConclusionsThe incidence of AWS is not negligible, describing prolonged responses after AA withdrawal, including the possibility of increased overall survival. These results could entail new treatment schemes for mCRPC.

Factores predictivos del síndrome de retirada de abiraterona

Introduction and objectiveAbiraterone withdrawal syndrome (AWS) is characterized by a transient decrease in the PSA after abiraterone acetate (AA) treatment discontinuation in patients diagnosed with metastatic castration-resistant prostate cancer (mCRPC). The aim of our study is to identify the possible predictive factors of AWS at diagnosis. Materials and methodsWe performed a retrospective study of 70 patients treated with AA at the Institut Català d’Oncologia – L’Hospitalet between 2015 and 2017. Results11 patients presented AWS. The mean age at diagnosis was 65.73 years and the mean age of presentation was 74.18 years. Patients were in the ninth treatment cycle. The median PSA was: 30.5ng/ml at diagnosis, 33.24ng/ml in the AWS, and 15.78ng/ml before starting another treatment. The median follow-up period after AWS was 8.2 months. The predictive factors of AWS would be: high PSA (p=.002), ISUP≥4 (p=.002) and stage IV at diagnosis (p<.001). Patients with a T stage present high risk, but without statistical significance. An AUC of 0.84 was obtained, with a 95% CI between 0.77 and 0.92 (p<.001). ConclusionsThe incidence of AWS is not negligible, describing prolonged responses after AA withdrawal, including the possibility of increased overall survival. These results could entail new treatment schemes for mCRPC.

4 - Predicting abiraterone acetate treatment resistance from blood-circulating androgen receptor variants in castration-resistant prostate cancer

4 - Predicting abiraterone acetate treatment resistance from blood-circulating androgen receptor variants in castration-resistant prostate cancer

Abiraterone acetate treatment in patients with castration-resistant prostate cancer with visceral metastases: a real-world experience.

In the pre-chemotherapy (CT) and post-CT settings of metastatic castration-resistant prostate cancer (mCRPC), abiraterone acetate plus prednisone (AAP) significantly extended median overall survival and radiographic progression-free survival (PFS) compared with prednisone alone. Yet, few data are available on therapy efficacy in the subgroup with visceral metastases, who represent a small population with poor prognosis. The aim of this study was to describe the clinical experience of AAP in patients with mCRPC with liver and/or lung metastases in real-world setting. We retrospectively reviewed the clinical records of patients with mCRPC with liver and/or lung metastases treated at the National Cancer Institute 'Fondazione G. Pascale' from September 2011 to May 2017. Co-primary end points were overall survival and radiographic PFS. Survival estimates were computed using Kaplan-Meier method. Secondary end points were response rate and safety. Of 143 patients with mCRPC treated, 18.9% (N=27) had visceral metastases: 85.2% (N=23) of the lung, 11.1% (N=3) of the liver and 3.7% (N=1) of both. Median PFS was 13.1 months [95% confidence interval (CI): 4.8-NA] in the pre-CT setting (N=11, median follow-up: 12.9 months), and 10.5 months (95% CI: 4.4-16.6) in the post-CT setting (N=16, median follow-up: 17.2 months). Pre-CT and post-CT patients with lung metastases had a median PFS of 16.5 months (95% CI: 4.3-NA) and 11.4 months (95% CI: 4.2-17.0), respectively. AAP tolerability was consistent with that previously reported in patients with mCRPC, without new safety concerns. Our finding provides preliminary evidence that AAP in real-world setting is a potential effective and safe therapeutic option for patients with mCRPC with a more advanced disease associated with the presence of visceral metastases, in both the pre-CT and post-CT settings.

A Cost-effectiveness Analysis of Systemic Therapy for Metastatic Hormone-sensitive Prostate Cancer

BackgroundFollowing the recent publication of results from randomized trials that have demonstrated a survival benefit for the addition of docetaxel or abiraterone acetate to androgen deprivation therapy (ADT) in the treatment of metastatic prostate cancer, it is important to assess whether the benefits of treatment with these agents outweigh their costs. ObjectiveTo perform a cost-effectiveness analysis of immediate docetaxel or abiraterone acetate treatment in addition to ADT in men with metastatic hormone-sensitive prostate cancer (PC). Design, setting, and participantsWe developed a state-transition model to simulate the natural progression of metastatic PC. Model parameters were derived from the published literature and through calibration to observed epidemiological data. Following diagnosis, a hypothetical cohort of men with metastatic hormone-sensitive PC could be treated with docetaxel+ADT, abiraterone+ADT, or ADT alone. Once disease progresses to castration-resistant PC, treatment with one of the approved therapies in this setting was initiated. Outcome measurements and statistical analysisThe outcomes measured were quality-adjusted life years (QALYs) and costs from a US private payer, health sector perspective. Results and limitationsCompared to treatment with ADT alone, docetaxel and abiraterone resulted in a discounted quality-adjusted survival gain of 3.6 and 22.0mo, respectively. Using standard cost-effectiveness metrics, treatment with docetaxel and ADT provides high value for money (ie, is cost effective) with an incremental cost-effectiveness ratio (ICER) of $34723, compared to an ICER of $295212 for abiraterone. The monthly cost of abiraterone would have to be less than $3114 for it to be cost effective. ConclusionsDocetaxel+ADT is likely the most cost-effective treatment option for men with metastatic hormone-sensitive PC. Although potentially more effective than docetaxel, the costs of abiraterone would have to be considerably lower to match the cost effectiveness of docetaxel+ADT. Patient summaryThis study evaluated the balance of costs and benefits for treatment of metastatic hormone-sensitive prostate cancer with docetaxel plus androgen deprivation therapy (ADT), abiraterone plus ADT, or ADT alone. We found that treatment with docetaxel plus ADT likely represents the most cost-effective option in this setting.

Patient Preferences for Metastatic Hormone-Sensitive Prostate Cancer Treatments: A Discrete Choice Experiment Among Men in Three European Countries.

IntroductionVarious treatment options are available for metastatic hormone-sensitive prostate cancer. This study aimed to quantify how men with prostate cancer in the United Kingdom (UK), Germany, and Spain perceive the risks and benefits of hypothetical abiraterone acetate plus prednisone treatment and docetaxel-based chemotherapy treatment options.MethodsA targeted literature review, exploratory interviews with prostate cancer patients and oncologists, and pre-test interviews were used to develop a discrete choice experiments (DCE). The final DCE included 32 choice sets, selected using a main-effects orthogonal design, divided into two survey blocks. Paired profiles presented hypothetical treatments for prostate cancer through six attributes that could be presented at two or four levels each. Preference estimates were estimated using a conditional logit regression model. Preference results were stratified by cancer stage.ResultsA total of 152 participants (mean age 69 years) completed the DCE in the UK, Germany, and Spain. Treatment effectiveness was the main concern for the patients (difference in preference estimates between 8 and 32 months 1.443). Participants wanted to avoid pain that was not well controlled (preference dummy coding estimate − 1.157). Participants valued a change from an oral medication to an intravenous treatment (change in preference estimate − 0.416) more negatively than a change from a 1% to a 5% risk of infection (change in preference estimate − 0.313).ConclusionsThis study shows that treatment effectiveness and pain control were the most important attributes for patients with prostate cancer. These two attributes influenced more than 50% of their decision-making in this study. The risk of fatigue and mode of administration were least prioritised by patients. This study highlights the relative importance that Spanish, German, and British patients place on various aspects of treatment options for prostate cancer. Understanding patient preference and taking them into consideration shall help physicians when developing their treatment strategies for their patients.FundingJanssen.Electronic supplementary materialThe online version of this article (10.1007/s12325-018-0861-3) contains supplementary material, which is available to authorized users.