Evaluation of adherence to abiraterone therapy in prostate cancer patients based on a population pharmacokinetic model.

AIMS: Abiraterone treatment requires regular drug intake under fasting conditions due to pronounced food effect, which may impact patient adherence. The aim of this prospective study was to evaluate adherence to abiraterone treatment in patients with prostate cancer. To achieve this aim, an abiraterone population pharmacokinetic model was developed and patients' adherence has been estimated by comparison of measured levels of abiraterone with population model-based simulations. METHODS: A total of 1469 abiraterone plasma levels from 83 healthy volunteers collected in a bioequivalence study were analysed using a nonlinear mixed-effects model. Monte Carlo simulation was used to describe the theoretical distribution of abiraterone pharmacokinetic profiles at a dose of 1000 mg once daily. Adherence of 36 prostate cancer patients treated with abiraterone was then evaluated by comparing the real abiraterone concentration measured in each patient during follow-up visit with the theoretical distribution of profiles based on simulations. Patients whose abiraterone levels were ˂5th or ˃95th percentile of the distribution of simulated profiles were considered to be non-adherent. RESULTS: Based on this evaluation, 13 patients (36%) have been classified as non-adherent. We observed significant association (P = .0361) between richness of the breakfast and rate of non-adherence. Adherent patients reported significantly better overall condition in self-assessments (P = .0384). A trend towards a higher occurrence of adverse effects in non-adherent patients was observed. CONCLUSIONS: We developed an abiraterone population pharmacokinetic model and proposed an advanced approach to medical adherence evaluation. Due to the need for administration under fasting conditions, abiraterone therapy is associated with a relatively high rate of non-adherence.

Long-Term Pharmacokinetic Follow-Up of Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer.

This ABIGENE pharmacokinetic (PK) study sought mainly to characterize the unchanged drug PK during long-term abiraterone acetate (AA) administration in advanced prostate cancer patients (81 patients). It was observed that individual AA concentrations remained constant over treatment time, with no noticeable changes during repeated long-term drug administration for up to 120 days. There was no correlation between AA concentrations and survival outcomes. However, a significant association between higher AA concentrations and better clinical benefit was observed (p = 0.041). The safety data did not correlate with the AA PK data. A significant positive correlation (r = 0.40, p < 0.001) was observed between mean AA concentration and patient age: the older the patient, the higher the AA concentration. Patient age was found to impact steady-state AA concentration: the older the patient, the higher the mean AA concentration. Altogether, these data may help to guide future research and clinical trials in order to maximize the benefits of AA metastatic castration-resistant prostate cancer patients.

Plasma microRNA Signature as Companion Diagnostic for Abiraterone Acetate Treatment in Metastatic Castration-Resistant Prostate Cancer: A Pilot Study.

Abiraterone acetate (AA) serves as a medication for managing persistent testosterone production in patients with metastatic castration-resistant prostate cancer (mCRPC). However, its efficacy varies among individuals; thus, the identification of biomarkers to predict and follow treatment response is required. In this pilot study, we explored the potential of circulating microRNAs (c-miRNAs) to stratify patients based on their responsiveness to AA. We conducted an analysis of plasma samples obtained from a cohort of 33 mCRPC patients before and after three, six, and nine months of AA treatment. Using miRNA RT-qPCR panels for candidate discovery and TaqMan RT-qPCR for validation, we identified promising miRNA signatures. Our investigation indicated that a signature based on miR-103a-3p and miR-378a-5p effectively discriminates between non-responder and responder patients, while also following the drug's efficacy over time. Additionally, through in silico analysis, we identified target genes and transcription factors of the two miRNAs, including PTEN and HOXB13, which are known to play roles in AA resistance in mCRPC. In summary, our study highlights two c-miRNAs as potential companion diagnostics of AA in mCRPC patients, offering novel insights for informed decision-making in the treatment of mCRPC.

Dynamic assessment of serum chromogranin A and treatment response with abiraterone acetate in metastatic castration-resistant prostate cancer.

OBJECTIVE: Elevated serum chromogranin A (CGA) is associated with intrinsic or treatment-related neuroendocrine differentiation (NED) in men with metastatic castration-resistant prostate cancer (mCRPC). Fluctuations in serum CGA during treatment of mCRPC have had conflicting results. We analyzed the impact of (i) rising serum CGA and (ii) baseline CGA/PSA ratio during treatment to identify associations with abiraterone acetate (AA) therapy. METHODS: Between June 2013 and August 2015, 92 men with mCRPC were enrolled in a prospective trial with uniform serum CGA processing performed before initiating abiraterone acetate/prednisone (AA/P) and serially after 12 weeks of AA/P treatments. Serum CGA was measured using a homogenous automated immunofluorescent assay. Patients receiving proton pump inhibitors or with abnormal renal function were excluded due to possible false elevations of serum CGA (n = 21 excluded), therefore 71 patients were analyzed. All patients underwent a composite response assessment at 12-weeks. Kaplan-Meier estimates and Cox Regression models were used to calculate the association with time-to-treatment failure analyses and overall survival. RESULTS: An increase in chromogranin was associated with a lower risk of treatment failure (hazard ratio [HR]: 0.52, p = 0.0181). The median CGA/PSA ratio was 7.8 (2.6-16.0) and an elevated pretreatment CGA/PSA ratio above the median was associated with a lower risk of treatment failure (HR: 0.54 p value = 0.0185). An increase in CGA was not found to be associated with OS (HR: 0.71, 95% CI: 0.42-1.21, p = 0.207). An elevated baseline CGA/PSA ratio was not associated with OS (HR: 0.62, 95% CI: 0.37-1.03, p = 0.062). An increase in PSA after 12 weeks of treatment was associated with an increased risk of treatment failure (HR: 4.14, CI: 2.21-7.73, p = < 0.0001) and worse OS (HR: 2.93, CI: 1.57-4.45, p = < 0.0001). CONCLUSIONS: We show that an increasing chromogranin on AA/P and an elevated baseline CGA/PSA in patients with mCRPC were associated with a favorable response to AA/P with no changes in survival. There may be limited clinical utility in serum CGA testing to evaluate for lethal NED as AA/P did not induce lethal NED in this cohort. This highlights that not all patients with an increasing CGA have a worse OS.

Cardiovascular outcomes among patients with castration-resistant prostate cancer: A comparative safety study using US administrative claims data.

BACKGROUND: Cardiovascular conditions are the most prevalent comorbidity among patients with prostate cancer, regardless of treatment. Additionally, cardiovascular risk has been shown to increase following exposure to certain treatments for advanced prostate cancer. There is conflicting evidence on risk of overall and specific cardiovascular outcomes among men treated for metastatic castrate resistant prostate cancer (CRPC). We, therefore, sought to compare incidence of serious cardiovascular events among CRPC patients treated with abiraterone acetate plus predniso(lo)ne (AAP) and enzalutamide (ENZ), the two most widely used CRPC therapies. METHODS: Using US administrative claims data, we selected CRPC patients newly exposed to either treatment after August 31, 2012, with prior androgen deprivation therapy (ADT). We assessed incidence of hospitalization for heart failure (HHF), ischemic stroke, and acute myocardial infarction (AMI) during the period 30-days after AAP or ENZ initiation to discontinuation, outcome occurrence, death, or disenrollment. We matched treatment groups on propensity-scores (PSs) to control for observed confounding to estimate the average treatment effect among the treated (AAP) using conditional Cox proportional hazards models. To account for residual bias, we calibrated our estimates against a distribution of effect estimates from 124 negative-control outcomes. RESULTS: The HHF analysis included 2322 (45.1%) AAP initiators and 2827 (54.9%) ENZ initiators. In this analysis, the median follow-up times among AAP and ENZ initiators (after PS matching) were 144 and 122 days, respectively. The empirically calibrated hazard ratio (HR) estimate for HHF was 2.56 (95% confidence interval [CI]: 1.32, 4.94). Corresponding HRs for AMI and ischemic stroke were 1.94 (95% CI: 0.90, 4.18) and 1.25 (95% CI: 0.54, 2.85), respectively. CONCLUSIONS: Our study sought to quantify risk of HHF, AMI and ischemic stroke among CRPC patients initiating AAP relative to ENZ within a national administrative claims database. Increased risk for HHF among AAP compared to ENZ users was observed. The difference in myocardial infarction did not attain statistical significance after controlling for residual bias, and no differences were noted in ischemic stroke between the two treatments. These findings confirm labeled warnings and precautions for AAP for HHF and contribute to the comparative real-world evidence on AAP relative to ENZ.

Niraparib with Abiraterone Acetate and Prednisone for Metastatic Castration-Resistant Prostate Cancer: Phase II QUEST Study Results.

Niraparib (NIRA) is a highly selective inhibitor of poly (adenosine diphosphate-ribose) polymerase, PARP1 and PARP2, which play a role in DNA repair. The phase II QUEST study evaluated NIRA combinations in patients with metastatic castration-resistant prostate cancer who were positive for homologous recombination repair gene alterations and had progressed on 1 prior line of novel androgen receptor-targeted therapy. Results from the combination of NIRA with abiraterone acetate plus prednisone, which disrupts androgen axis signaling through inhibition of CYP17, showed promising efficacy and a manageable safety profile in this patient population.

Visceral Metastasis Predicts Response to New Hormonal Agents in Metastatic Castration-Sensitive Prostate Cancer.

Visceral metastasis (VM) and a higher number of bone metastasis generally define high volume/risk in patients with metastatic castration-sensitive prostate cancer (mCSPC). Subgroup analysis of pivotal trials did not show a clear benefit of second-generation non-steroidal anti-androgens (NSAAs) in patients with VM. However, subgroup analysis of the trial assessing abiraterone acetate, a CYP 17 inhibitor, plus prednisone (AAP) showed an improved overall survival (OS) in patients with mCSPC with VM. We searched MEDLINE, Web of Science, and congress abstracts for the phase III randomized controlled trials of second-generation NSAAs and AAP in patients with mCSPC. In this pooled analysis, we included 6485 patients from the 6 phase III trials. The rate of patients with VM was 15.2%. Interestingly, in contrast to NSAAs, AAP seems to be effective in improving OS among patients with VM (hazard ratio, HR: 0.89, 95% CI, 0.72-1.11, P = .30 for second-generation NSAAs; HR: 0.58, 95% CI, 0.40-0.84, P = .004 for AAP). In contrast, both second-generation NSAAs (HR: 0.63, 95% CI, 0.57-0.70, P < .001) and AAP (HR: 0.68, 95% CI, 0.57-0.81, P < .001) improved OS in patients without VM. In this pooled analysis, we demonstrate that while AAP provided an OS improvement in patients with VM, second-generation NSAAs did not demonstrate a similar OS benefit in this population.

Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial.

BACKGROUND: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). PATIENTS AND METHODS: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. RESULTS: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. CONCLUSIONS: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.

Clinical impact of volume of disease and time of metastatic disease presentation on patients receiving enzalutamide or abiraterone acetate plus prednisone as first-line therapy for metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer remains a challenging condition to treat. Among the available therapeutic options, the androgen receptor signaling inhibitors abiraterone acetate plus prednisone (AA) and enzalutamide (Enza), are currently the most used first-line therapies in clinical practice. However, validated clinical indicators of prognosis in this setting are still lacking. In this study, we aimed to evaluate a prognostic model based on the time of metastatic disease presentation (after prior local therapy [PLT] or de-novo [DN]) and disease burden (low volume [LV] or high-volume [HV]) at AA/Enza onset for mCRPC patients receiving either AA or Enza as first-line. METHODS: A cohort of consecutive patients who started AA or Enza as first-line treatment for mCRPC between January 1st, 2015, and April 1st, 2019 was identified from the clinical and electronic registries of the 9 American and European participating centers. Patients were classified into 4 cohorts by the time of metastatic disease presentation (PLT or DN) and volume of disease (LV or HV; per the E3805 trial, HV was defined as the presence of visceral metastases and/or at least 4 bone metastases of which at least 1 out the axial/pelvic skeleton) at AA/Enza onset. The endpoint was overall survival defined as the time from AA or Enza initiation, respectively, to death from any cause or censored at the last follow-up visit, whichever occurred first. RESULTS: Of the 417 eligible patients identified, 157 (37.6%) had LV/PLT, 87 (20.9%) LV/DN, 64 (15.3%) HV/PLT, and 109 (26.1%) HV/DN. LV cohorts showed improved median overall survival (59.0 months; 95% CI, 51.0-66.9 months) vs. HV cohorts (27.5 months; 95% CI, 22.8-32.2 months; P = 0.0001), regardless of the time of metastatic presentation. In multivariate analysis, HV cohorts were confirmed associated with worse prognosis compared to those with LV (HV/PLT, HR = 1.87; p = 0.029; HV/DN, HR = 2.19; P = 0.002). CONCLUSION: Our analysis suggests that the volume of disease could be a prognostic factor for patients starting AA or Enza as first-line treatment for metastatic castration-resistant prostate cancer, pending prospective clinical trial validation.

Development and validation of a survival nomogram and calculator for male patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate and/or enzalutamide.

BACKGROUND: Despite the widespread availability of medication choices for metastatic castration-resistant prostate cancer (mCRPC), biomarkers to predict the efficacy of each mCRPC treatment have not yet been established. This study developed a prognostic nomogram and a calculator to predict the prognosis of patients with mCRPC who received abiraterone acetate (ABI) and/or enzalutamide (ENZ). METHODS: In total, 568 patients with mCRPC who underwent ABI and/or ENZ between 2012 and 2017 were enrolled. A prognostic nomogram based on the risk factors was developed using the Cox proportional hazards regression model and clinically important factors. The discriminatory ability of the nomogram was assessed according to the concordance index (C-index). A 5-fold cross-validation was repeated 2000 times to estimate the C-index, and the means of the estimated C-index for the training and validation sets were determined. A calculator based on this nomogram was then developed. RESULTS: The median overall survival (OS) was 24.7 months. Multivariate analysis showed that the time to CRPC, pre-chemotherapy, baseline prostate-specific antigen, baseline alkaline phosphatase, and baseline lactate dehydrogenase levels were independent risk factors for OS (hazard ratio [HR]: 0.521, 1.681, 1.439, 1.827, and 12.123, p = 0.001, 0.001, < 0.001, 0.019, and < 0.001, respectively). The C-index was 0.72 in the training cohort and 0.71 in the validation cohort. CONCLUSIONS: We developed a nomogram and calculator to predict OS in Japanese patients with mCRPC who received ABI and/or ENZ. Reproducible prognostic prediction calculators for mCRPC will facilitate greater accessibility for clinical use.

Survival outcomes and prognostic factors for first-line abiraterone acetate or enzalutamide in patients with metastatic castration-resistant prostate cancer.

PURPOSE: To investigate the survival outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line novel androgen receptor axis-targeted therapies (ARATs) and prognostic factors for patient survival. METHODS: This retrospective study obtained data from 202 patients who started abiraterone acetate or enzalutamide as first-line therapy for mCRPC between 2016 and 2021 from a single academic center. The primary endpoint was overall survival (OS) defined as the interval from the start of ARAT to death, loss to follow-up, or the end of the study period. The secondary endpoints were PSA decline, PSA nadir, and time to nadir (TTN) after ARATs. Kaplan-Meier survival analyses were applied for depicting OS. Cox proportional hazards model with inversed probability of treatment weighing-adjustment was used to validate the effect of patient, disease, and treatment response factors on OS. RESULTS: Among 202 patients, 164 patients were treated with first-line ARATs alone and 38 patients received second-line chemotherapy. The median OS was not reached in patients with first-line ARATs alone and was 38.8 months in those with subsequent chemotherapy after failure from ARATs. OS was not different between the use of abiraterone and enzalutamide, though enzalutamide showed a higher rate of PSA decline ≧ 90% (56% versus 40%, p = 0.021) and longer TTN (5.5 versus 4.7 months, p = 0.019). Multivariable analysis showed that PSA nadir > 2 ng/mL [hazard ratio (HR) 7.04, p < 0.001] and TTN<7 months (HR 2.18, p = 0.012) were independently associated with shorter OS. Patients with both of these poor prognostic factors had worse OS compared to those who had 0-1 factors (HR 9.21, p < 0.001). CONCLUSIONS: Patients with mCRPC who received first-line ARATs had better survival if they had a PSA nadir[Formula: see text]2 ng/mL or a TTN[Formula: see text]7 months. Further study is needed to determine if an early switch in therapy for those in whom neither is achieved may impact OS.

Cortisol as Biomarker for CYP17-Inhibition is Associated with Therapy Outcome of Abiraterone Acetate.

BACKGROUND: Abiraterone acetate is an irreversible 17α-hydroxylase/C17, 20-lyase (CYP17) inhibitor approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients. Inhibition of this enzyme leads to low testosterone and cortisol levels in blood. There is growing evidence that clinical efficacy of abiraterone is related to the rate of suppression of serum testosterone. However, quantification of very low levels of circulating testosterone is challenging. We therefore aimed to investigate whether circulating cortisol levels could be used as a surrogate biomarker for CYP17 inhibition in patients with mCRPC treated with abiraterone acetate. PATIENTS AND METHODS: mCRPC patients treated with abiraterone acetate were included. Abiraterone and cortisol levels were measured with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). On treatment cortisol and abiraterone concentrations were related to treatment response and progression free survival. RESULTS: In total 117 patients were included with a median cortisol concentration of 1.13 ng/ml (range: 0.03 - 82.2) and median abiraterone trough concentration (Cmin) of 10.2 ng/ml (range: 0.58 - 92.1). In the survival analyses, abiraterone Cmin ≥ 8.4 ng/mL and cortisol < 2.24 ng/mL were associated with a longer prostate-specific antigen (PSA) independent progression-free survival than patients with an abiraterone concentration ≥ 8.4 ng/mL and a cortisol concentration ≥ 2.24 ng/mL (13.8 months vs. 3.7 months). CONCLUSION: Our study shows that cortisol is not an independent predictor of abiraterone response in patients with mCRPC, but it is of added value in combination with abiraterone levels, to predict a response on abiraterone.

Impact of trough abiraterone level on adverse events in patients with prostate cancer treated with abiraterone acetate.

PURPOSE: We assessed the impact of plasma trough concentrations of abiraterone (ABI) and its metabolite Δ4-abiraterone (D4A) and related polymorphisms on adverse events (AEs) in patients with metastatic prostate cancer who received abiraterone acetate (AA). METHODS: This prospective study enrolled patients with advanced prostate cancer treated with AA between 2016 and 2021. Plasma trough concentrations of ABI and D4A were measured using high-performance liquid chromatography. The impact of HSD3B1 rs1047303, SRD5A2 rs523349, and cytochrome P450 family 3A member 4 rs2242480 polymorphisms on plasma concentrations of ABI and D4A and the incidence of AEs were also assessed. RESULTS: In 68 patients treated with AA, the median ABI and D4A concentrations were 18.1 and 0.94 ng/mL, respectively. The high plasma trough concentration of ABI (≥ 20.6 ng/mL) was significantly associated with the presence of any AE and its independent risk factor based on multivariable analysis (odds ratio, 7.20; 95% confidence interval (CI): 2.20-23.49). Additionally, a high plasma trough concentration of ABI was an independent risk factor of time to withdraw AA (hazard ratio, 4.89; 95% CI: 1.66-14.38). The risk alleles of three polymorphisms were not statistically associated with the ABI and D4A concentrations and the incidence of AEs. CONCLUSIONS: The plasma trough concentration of ABI is associated with the presence of AEs and treatment failure after AA administration. ABI concentration monitoring may be useful in patients with prostate cancer who received AA.

Novel hormonal therapies in the management of advanced prostate cancer: extrapolating Asian findings to Southeast Asia.

There is a paucity of information on the use of novel hormonal agents in Southeast Asian patients. We reviewed the clinical roles of novel hormonal therapy (NHT), namely abiraterone acetate (AA), enzalutamide, apalutamide and darolutamide, in the management of advanced prostate cancer, and data on its use in Asian patients, in order to extrapolate these findings to the Southeast Asian patient population. There are some differences in the molecular features between the NHTs, which influenced their respective permeabilities through the blood-brain barrier. The Asian sub-analyses of the landmark studies of each NHT were limited. The primary endpoints of the Asian sub-analyses generally reflect the efficacy outcomes of the respective landmark study. Hypertension, fatigue, musculoskeletal disorders, rash, and hot flushes were among the common toxicities observed in Asian patients. Real-world data on AA in the Asian setting is favourable, but data is limited for enzalutamide, apalutamide and darolutamide. Based on the sub-analyses and real-world data, the efficacy and safety of NHTs in the Asian patients showed a similar trend to the respective landmark studies. The lack of clinical trials in the Southeast Asian region hampers the ability to make a robust conclusion on any specific efficacy or safety differences that may be present; clinicians must assume that the broader Asian sub-analyses and real-world data reflects Southeast Asian patients' outcomes.

Augmented experimental design for bioavailability enhancement: a robust formulation of abiraterone acetate.

Abiraterone acetate (ABRTA) is clinically beneficial in management of metastatic castration-resistant prostate cancer (PC-3). With highlighted low solubility and permeability, orally hampered treatment of ABRTA necessitate high dose to achieve therapeutic efficacy. To triumph these challenges, we aimed to develop intestinal lymphatic transport facilitating lipid-based delivery to enhance bioavailability. ABRTA-containing self-nano emulsified drug delivery (ABRTA-SNEDDS) was statistically optimized by D-optimal design using design expert. Optimized formulation was characterized for particle size, thermodynamic stability, in vitro release, in vivo bioavailability, intestinal lymphatic transport, in vitro cytotoxic effect, anti-metastatic activity, and apoptosis study. Moreover, hemolysis and histopathology studies have been performed to assess pre-clinical safety. Nano-sized particles and successful saturated drug loading were obtained for optimized formulation. In vitro release upto 98.61 ± 3.20% reveal effective release of formulation at intestinal pH 6.8. ABRTA-SNEDDS formulation shows enhanced in vivo exposure of Abiraterone (2.5-fold) than ABRTA suspension in Sprague-Dawley rats. In vitro efficacy in PC-3 cell line indicates 3.69-fold higher therapeutic potential of nano drug delivery system. Hemolysis and histopathology study indicates no significant toxicities to red blood cells and tissues, respectively. Apparently, an opportunistic strategy to increasing bioavailability of ABRTA via intestinal lymphatic transport will create a viable platform in rapidly evolving chemotherapy. Enhanced translational utility of delivery was also supported through in vitro therapeutic efficacy and safety assessments. HighlightsAbiraterone acetate is a prostate cancer drug, impeded with low bioavailability.ABRTA loaded in self nano emulsifying drug delivery enhanced its bioavailability.Intestinal lymphatic transport played role in enhanced bioavailability of ABRTA.ABRTA-SNEDDS enhanced in vitro cytotoxic activity of ABRTA.ABRTA-SNEDDS found safe in preclinical safety evaluations.

Plasmatic MicroRNAs and Treatment Outcomes of Patients with Metastatic Castration-Resistant Prostate Cancer: A Hospital-Based Cohort Study and In Silico Analysis.

Prostate cancer (PCa) is one of the most common malignancies among men worldwide. Inevitably, all advanced PCa patients develop metastatic castration-resistant prostate cancer (mCRPC), an aggressive phase of the disease. Treating mCRPC is challenging, and prognostic tools are needed for disease management. MicroRNA (miRNA) deregulation has been reported in PCa, constituting potential non-invasive prognostic biomarkers. As such, this study aimed to evaluate the prognostic potential of nine miRNAs in the liquid biopsies (plasma) of mCRPC patients treated with second-generation androgen receptor axis-targeted (ARAT) agents, abiraterone acetate (AbA) and enzalutamide (ENZ). Low expression levels of miR-16-5p and miR-145-5p in mCRPC patients treated with AbA were significantly associated with lower progression-free survival (PFS). The two miRNAs were the only predictors of the risk of disease progression in AbA-stratified analyses. Low miR-20a-5p levels in mCRPC patients with Gleason scores of <8 were associated with worse overall survival (OS). The transcript seems to predict the risk of death regardless of the ARAT agent. According to the in silico analyses, miR-16-5p, miR-145-5p, and miR-20a-5p seem to be implicated in several processes, namely, cell cycle, proliferation, migration, survival, metabolism, and angiogenesis, suggesting an epigenetic mechanism related to treatment outcome. These miRNAs may represent attractive prognostic tools to be used in mCRPC management, as well as a step further in the identification of new potential therapeutic targets, to use in combination with ARAT for an improved treatment outcome. Despite the promising results, real-world validation is necessary.

Abiraterone acetate versus nonsteroidal antiandrogen with androgen deprivation therapy for high-risk metastatic hormone-sensitive prostate cancer.

BACKGROUND: Although prostate cancer is a very common form of malignancy in men, the clinical significance of androgen deprivation therapy (ADT) with abiraterone acetate versus the nonsteroidal antiandrogen bicalutamide has not yet been verified in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). The present study was designed to initiate this verification in real-world Japanese clinical practice. METHODS: We retrospectively analyzed the records of 312 patients with high-risk mHSPC based on LATITUDE criteria and had received ADT with bicalutamide (n = 212) or abiraterone acetate (n = 100) between September 2015 and December 2020. Bicalutamide was given at 80 mg daily and abiraterone was given at 1000 mg daily as four 250-mg tablets plus prednisolone (5-10 mg daily). Overall survival (OS), cancer-specific survival (CSS), and time to castration-resistant prostate cancer (CRPC) were compared. The prognostic factor for time to CRPC was analyzed by Cox proportional hazard model. RESULTS: Patients in the bicalutamide group were older, and more of them had poor performance status (≧2), than in the abiraterone group. Impaired liver function was noted in 2% of the bicalutamide group and 16% of the abiraterone group (p < 0.001). Median follow-up was 22.5 months for bicalutamide and 17 months for abiraterone (p < 0.001). Two-year OS and CSS for bicalutamide versus abiraterone was 77.8% versus 79.5% (p = 0.793) and 81.1% versus 82.5% (p = 0.698), respectively. Median time to CRPC was significantly longer in the abiraterone group than in the bicalutamide group (NA vs. 13 months, p < 0.001). In multivariate analysis, Gleason score ≧9, high alkaline phosphatase, high lactate dehydrogenase, liver metastasis, and bicalutamide were independent prognostic risk factors for time to CRPC. Abiraterone prolonged the time to CRPC in patients with each of these prognostic factors. CONCLUSIONS: Despite limitations regarding the time-dependent bias, ADT with abiraterone acetate significantly prolonged the time to CRPC compared to bicalutamide in patients with high-risk mHSPC. However, further study with longer follow-up is needed.

Prognostic role of pan-immune-inflammation value in patients with metastatic castration-resistant prostate cancer treated with androgen receptor-signaling inhibitors.

AIM: To assess the prognostic effect of pan-immune inflammation value (PIV) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA) or enzalutamide. METHODS: Patients with mCRPC treated with AA or enzalutamide between January 2010 and June 2021 were included in this study. The most recently examined complete blood count values in the 1-month period before treatment were used for calculating PIV. The relationship between overall survival (OS) and PIV was evaluated by multivariate analysis. By using PIV and lactate dehydrogenase (LDH) levels which had shown survival effect at multivariate analysis, PIV-LDH combined score was established. RESULTS: A total of 114 patients were included in this study. At the median follow-up of 34.6 months (95% confidence interval [CI]: 32.4-36.8), the median OS was 21 months (95% CI: 17.6-21.3). The median OS in the low-PIV group was significantly higher than in the high-PIV group (34.4 months (95% CI: 21.3-47.5) vs. 14.3 months (95% CI: 10.0-18.7), p < 0.001). In the multivariate analysis for OS, high PIV (hazard ratio [HR]: 1.86, 95% CI: 1.11-3.13, p = 0.018) and LDH value 1.5 times the upper limit of normal and above (HR: 3.65 95%, CI: 1.86-7.16, p < 0.001) were associated with shorter OS. When survival analysis was performed according to the PIV-LDH combined score, the median OS was 34.4 months (95% CI: 22.2-46.6) in the low-risk group, 17.7 months (95% CI: 11.7-23.6) in the intermediate-risk group, and 8.4 months (95% CI: 5.1-11.7) in the high-risk group (p < 0.001). The C-index of the combined PIV-LDH score was higher than the C-index of PIV (0.65 vs. 0.61). CONCLUSION: In this study, we demonstrated that PIV was an independent prognostic factor for OS in patients with mCRPC treated with AA or enzalutamide. Additionally, PIV-LDH combined score may be considered a promising composite peripheral blood-based biomarker to predict OS in those patients.

P2Y1 agonist HIC in combination with androgen receptor inhibitor abiraterone acetate impairs cell growth of prostate cancer.

P2Y receptors belong to the large superfamily of G-protein-coupled receptors and play a crucial role in cell death and survival. P2Y1 receptor has been identified as a marker for prostate cancer (PCa). A previously unveiled selective P2Y1 receptor agonist, the indoline-derived HIC (1-(1-((2-hydroxy-5-nitrophenyl)(4-hydroxyphenyl)methyl)indoline-4-carbonitrile), induces a series of molecular and biological responses in PCa cells PC3 and DU145, but minimal toxicity to normal cells. Here, we evaluated the combinatorial effect of HIC with abiraterone acetate (AA) targeted on androgen receptor (AR) on the inhibition of PCa cells. Here, the presence of HIC and AA significantly inhibited cell proliferation of PC3 and DU145 cells with time-dependent manner as a synerfistic combination. Moreover, it was also shown that the anticancer and antimetastasis effects of the combinratorial drugs were noticed through a decrease in colony-forming ability, cell migration, and cell invasion. In addition, the HIC + AA induced apoptotic population of PCa cells as well as cell cycle arrest in G1 progression phase. In summary, these studies show that the combination of P2Y1 receptor agonist, HIC and AR inhibitor, AA, effectively improved the antitumor activity of each drug. Thus, the combinatorial model of HIC and AA should be a novel and promising therapeutic strategy for treating prostate cancer.

Sex Hormones and Prostate Cancer.

The prostate is an androgen-dependent organ that develops only in male mammals. Prostate cancer is the most common nonskin malignancy in men and the second leading cause of cancer deaths. Metastatic prostate cancer initially retains its androgen dependence, and androgen-deprivation therapy often leads to disease control; however, the cancer inevitably progresses despite treatment as castration-resistant prostate cancer, the lethal form of the disease. Although it was assumed that the cancer became androgen independent during this transition, studies over the last two decades have shown that these tumors evade treatment via mechanisms that augment acquisition of androgens from circulating precursors, increase sensitivity to androgens and androgen precursors, bypass the androgen receptor, or a combination of these mechanisms. This review summarizes the history of prostate cancer research leading to the contemporary view of androgen dependence for prostate cancers and the current treatment approaches based on this modern paradigm.