Efficacy Of Abiraterone Acetate Research Articles

The prognostic value of ductal adenocarcinoma of the prostate in patients with advanced prostate cancer treated with abiraterone acetate.

167 Background: Previous studies have indicated that ductal adenocarcinoma of the prostate (DA) is associated with adverse prognosis in patients with localized prostate cancer (PCa). However, the clinical significance of DA in advanced PCa remains largely ambiguous. This study endeavors to investigate the relationship between the existence of DA in prostate biopsy specimens and treatment outcomes among patients with advanced PCa receiving abiraterone acetate (AA) therapy. Methods: We retrospectively analyzed data from 440 patients with advanced PCa who received AA at either the metastatic hormone-sensitive (mHSPC, N=123) or castration-resistant PCa (mCRPC, N=317) stage. The presence of DA and its proportion was evaluated based on prostate biopsy specimens. Kaplan-Meier curves and COX regression were used to evaluate the predictive significance of DA on AA efficacy, including PSA response, PSA progression-free survival (PSA-PFS), and radiographic progression-free survival (rPFS). Results: In aggregate, DA was detected in 35/440 (8.0%) patients, with 13/440 (3.0%) and 22/440 (5.0%) men harboring DA<5% and ≥5%, respectively, in the total tumors. The overall PSA response rate in the entire cohort was 302/440 (68.6%), and it was comparable for people with and without DA, with both groups having a response rate of 68.6%. Of note, compared with patients without DA, men with DA have significantly longer median PSA-PFS (mPSA-PFS, 12.1- vs. 25.0-Mo, P=0.005) and median rPFS (mrPFS, 19.8 vs. 38.2-Mo, P=0.034). Subgroup analysis based on DA proportion further revealed that in comparison with PCa without DA, DA≥5% was an indicator of favorable PSA-PFS (HR, 95%CI: 0.28, 0.14-0.56, p<0.001) and rPFS (HR, 95%CI: 0.35, 0.18-0.72, p=0.004), while DA<5% was not. In multivariate COX regression analysis, after adjusting by clinicopathological factors, including mCRPC/mHSPC stage, ISUP grading, metastatic burden, pain score and pretreatment hemoglobin, alkaline phosphatase, and lactate dehydrogenase, DA≥5% was still independently associated with better therapeutic efficacy of AA treatment (PSA-PFS: HR, 95%CI: 0.36, 0.17-0.74, p<0.001; rPFS: HR, 95%CI: 0.47, 0.23-0.96, p=0.040). Conclusions: A DA proportion ≥5% in the tumor is related to improved treatment efficacy for individuals with advanced PCa receiving AA. Thus, in the pathological diagnosis of PCa, it is necessary to routinely report the presence and proportion of DA in order to aid with treatment decision-making.

Effectiveness and safety of abiraterone acetate in metastatic castration-sensitive prostate cancer patients of Western Odisha

Background: Metastatic castration sensitive prostate cancer has different modalities of management. However, with the arrival of abiraterone acetate (AA), the management of this condition has changed to a greater extent. Aims and Objectives: As a new molecule its effectiveness and safety are being evaluated in our patient population as a prospective observational study for 18 months. Materials and Methods: This study included 50 patients who were treated with AA according to the treating physician. The overall survival observed at 18 months was 88%. Results: There was a significant decrease in mean serum prostate-specific antigen level with treatment. About 60% of patients were completely adhered to the treatment. About 94% of patients experienced some form of adverse event and 10% of patients died in this study. Though the molecule has adverse effects, the overall survival of the patients has increased. Conclusion: The efficacy of AA was observed consistent with the time in metastatic castration-sensitive prostate cancer patients with manageable adverse events.

Efficacy and safety of abiraterone acetate plus prednisone and androgen deprivation therapy +/- docetaxel in older patients (≥70 years), with de novo metastatic-castration sensitive prostate cancer, compared to younger patients (<70 years): The PEACE-1 trial.

20 Background: Metastatic castration-sensitive prostate cancer (mCSPC) primarily affects older men (OM). In this post-hoc analysis we investigated the safety and efficacy of abiraterone acetate + prednisone (AAP) in older (≥ 70 years) and younger (< 70 years) patients in PEACE-1. Methods: Men with de novo mCSPC were allocated to standard of care (SOC), SOC + AAP, SOC + radiotherapy (RXT), or SOC + AAP + RXT in this 2x2 design phase 3 trial. SOC was initially androgen deprivation therapy (ADT) alone, then from Oct 2015 onwards, the use of docetaxel (D) was authorized as part of SOC (at the investigator’s discretion until 2017, then, following the publication of LATITUDE and STAMPEDE trials, accrual was restricted to men receiving ADT+ D). Efficacy and safety in OM included in PEACE-1 were analyzed with the same methods used in the overall trial (Lancet 2022; 399: 1695-1707). Results: A total of 741 younger men (YM) (63%) and 431 OM (37%) were randomized. OM presented with more altered PS (ECOG 1-2) (36% vs 26% p=0.0003) and less frequent use of docetaxel (D) as part of SOC (66% vs 51% p<0.0001) than YM. Hypertension (56,5% vs 38,2%, p<0,001) and diabetes mellitus type 2 (15,5% vs 11%, p=0,029) were significantly more frequent in OM. Median time to AAP discontinuation was shorter (30.0 months [95%CI= 22.1; 35.4] vs 41.4 [95%CI= 31.5; 54.0] independently of D use and more frequently due to adverse events or death in the older than younger population. The benefit of AAP on radiographic progression-free survival (rPFS) tended to decrease with age in the overall population: (HR 0.65, 95%CI 0.42-1.01) in OM vs (HR 0.49, 95%CI 0.35-0.69) for YM. The same trend was observed on overall survival (OS): (HR 0.95, 95%CI 0.72-1.25) for OM vs (HR: 0.73, 95%CI 0.58-0.92) for YM. On the other hand, in men fit to receive the SOC composed of ADT+D, the rPFS benefit of AAP was comparable in OM (HR 0.55, 95%CI 0.29-1.04) and in YM (HR 0.5, 95%CI 0.33-0.78). The OS benefit of AAP was: (HR 0.80, 95%CI 0.53-1.2) and (HR 0.71, 95%CI 0.52-0.95) in OM and YM, respectively. Safety data show that severe adverse events (grade 3-5) were more frequent in OM receiving AAP in comparison with YM (69% vs 61%) while there was no difference between older and YM not receiving AAP (48% vs 47%). Conclusions: This post-hoc analysis of PEACE-1 suggests that, in the overall population, OM derive a lower benefit, both in terms of rPFS and OS, from adding AAP to SOC versus YM. This decreased benefit is likely due to more toxicity leading to more frequent and earlier drug discontinuation. Importantly, in OM fit enough to receive ADT+D, the benefit of adding AAP to SOC was comparable to YM. Clinical trial information: NCT01957436 .

Predictive factors for the efficacy of abiraterone acetate therapy in high-risk metastatic hormone-sensitive prostate cancer patients.

There is a discrepancy in the efficacy of abiraterone acetate for overall survival (OS) in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). This study aimed to identify predictive factors for the efficacy of abiraterone acetate for OS in high-risk mHSPC patients by analyzing them over a longer observation period. Five hundred high-risk mHSPC patients were retrospectively identified at our hospital and affiliated hospitals in the Kindai Oncology Study Group and Kyoto Prefectural University of Medicine Oncology StudyGroup between December 2013 and March 2022. Two hundred patients were treated with abiraterone acetate (1000mg/day) plus prednisolone (5mg/day) combined with androgen deprivation therapy (ADT). A total of 300 patients were treated with bicalutamide (80mg/day) in combination with ADT. OS was not significantly different between the two treatments in the overall cohort (p = 0.1643). In the subgroup without Gleason pattern 5 at the primary lesion, OS was significantly better in patients treated with abiraterone acetate than in those treated with bicalutamide (p = 0.0192). In the subgroup with Gleason pattern 5 at the primary lesion, no significant difference was found between the two treatments (p = 0.1799). Univariate and multivariate analyses in the subgroup without Gleason pattern 5 at the primary lesion suggested that abiraterone therapy may be an important and independent predictor of OS in high-risk mHSPC patients. The presence of Gleason pattern 5 at the primary lesion may be a predictor for high-risk mHSPC patients who could benefit from abiraterone acetate treatment.

Randomized Phase 2 Trial of Abiraterone Acetate Plus Prednisone, Degarelix, or the Combination in Men with Biochemically Recurrent Prostate Cancer After Radical Prostatectomy

BackgroundPhase 2 trial endpoints that can be utilized in high-risk biochemical recurrence (BCR) after prostatectomy as a way of more rapidly identifying treatments for phase 3 trials are urgently needed. The efficacy of abiraterone acetate plus prednisone (AAP) in BCR is unknown. ObjectiveTo compare the rates of complete biochemical responses after testosterone recovery after 8 mo of AAP and degarelix, a gonadotropin-releasing hormone antagonist, alone or in combination. Design, setting, and participantsPatients with BCR (prostate-specific antigen [PSA] ≥1.0 ng/ml, PSA doubling time ≤9 mo, no metastases on standard imaging, and testosterone ≥150 ng/dl) after prostatectomy (with or without prior radiotherapy) were included in this study. InterventionPatients were randomized to AAP (arm 1), AAP with degarelix (arm 2), or degarelix (arm 3) for 8 mo, and monitored for 18 mo. Outcome measurements and statistical analysisThe primary endpoint was undetectable PSA with testosterone >150 ng/dl at 18 mo. Secondary endpoints were undetectable PSA at 8 mo and time to testosterone recovery. Results and limitationsFor the 122 patients enrolled, no difference was found between treatments for the primary endpoint (arm 1: 5.1% [95% confidence interval {CI}: 1–17%], arm 2: 17.1% [95% CI: 7–32%], arm 3: 11.9% [95% CI: 4–26%]; arm 1 vs 2, p = 0.93; arm 2 vs 3, p = 0.36). AAP therapy showed the shortest median time to testosterone recovery (36.0 wk [95% CI: 35.9–36.1]) relative to degarelix (52.9 wk [95% CI: 49.0–56.0], p < 0.001). Rates of undetectable PSA at 8 mo differed between AAP with degarelix and degarelix alone (p = 0.04), but not between AAP alone and degarelix alone (p = 0.12). Limitations of this study include a lack of long-term follow-up. ConclusionsRates of undetectable PSA levels with testosterone recovery were similar between arms, suggesting that increased androgen suppression with AAP and androgen deprivation therapy (ADT) is unlikely to eradicate recurrent disease compared with ADT alone. Patient summaryWe evaluated the use of abiraterone acetate plus prednisone (AAP) and androgen deprivation therapy (ADT), AAP alone, or ADT alone in men with biochemically recurrent, nonmetastatic prostate cancer. While more men who received the combination had an undetectable prostate-specific antigen (PSA) level at 8 mo on treatment, once men came off treatment and testosterone level rose, there was no difference in the rates of undetectable PSA levels. This suggests that the combination is not able to eradicate disease any better than ADT alone.

Safety and efficacy of abiraterone acetate plus prednisolone in patients with castration-resistant prostate cancer: a prospective, observational, post-marketing surveillance study.

BackgroundAbiraterone acetate plus prednisolone is approved to treat patients with castration-resistant prostate cancer. This study evaluated the safety and efficacy of abiraterone acetate plus prednisolone in castration-resistant prostate cancer patients with or without previous chemotherapy in a real-world setting in Japan.MethodsThis study was an observational, prospective, post-marketing surveillance. Castration-resistant prostate cancer patients, who initiated abiraterone acetate after its approval in Japan, were enrolled. Data were collected during an observation period of 12 months and a follow-up period of another 12 months. Adverse events and adverse drug reactions were evaluated for safety. Prostate-specific antigen levels and overall survival were evaluated for efficacy.ResultsFrom 141 participating institutions, 497 patients were registered: 492 patients including 180 chemotherapy-naïve, 311 chemotherapy-experienced and one off-label-use patient received abiraterone and were evaluated for safety. Adverse events were observed in 225/492 patients (45.7%), adverse drug reactions in 131/492 patients (26.6%) and serious adverse drug reactions in 61/492 patients (12.4%). The most commonly observed adverse drug reaction was abnormal hepatic function (6.5%), followed by hypokalemia (3.0%) and decreased appetite (2.0%). At week 12, 110/432 patients (25.5%) achieved ≥50% decrease from baseline in prostate-specific antigen, and the proportion was higher in chemotherapy-naïve patients (56/161 patients; 34.8%) compared with chemotherapy-experienced patients (54/271 patients; 19.9%, P < 0.001). Survival rates at 24 months were 68.3% (295/432 patients), 73.9% (119/161 chemotherapy-naïve patients) and 64.9% (176/271 chemotherapy-experienced patients).ConclusionsThis large-scale, real-world, post-marketing surveillance study confirmed the safety and efficacy of abiraterone acetate plus prednisolone in Japanese castration-resistant prostate cancer patients with or without previous chemotherapy.

Cortisol as biomarker for CYP17 inhibition in mCRPC patients treated with abiraterone acetate.

5035 Background: Abiraterone acetate is an effective metastatic castration resistant prostate cancer (mCRPC) treatment, however, there is a high variability in response. It inhibits CYP17, thereby preventing the production of androgens. Abiraterone trough concentrations (Cmin) &gt; 8.4 ng/mL have been associated with an increased progression free survival (PFS) (Eur J Cancer. 2017;72:54-61; Prostate Cancer Prostatic Dis. 2020;23(2):244-251). However, plasma levels do not directly provide information on the level of CYP17 inhibition. Ideally, testosterone levels should be measured, but these levels are below the detection limit of available assays. The synthesis of cortisol is also inhibited by abiraterone via CYP17 inhibition and might therefore be a biomarker for CYP17 inhibition. The objective of this study was to investigate if cortisol levels are related to abiraterone levels and to clinical response. Methods: An observational study was performed in mCRPC patients treated with abiraterone acetate. At the outpatient clinic, plasma samples were collected for pharmacokinetic (PK) monitoring at each hospital visit. Reference populations of healthy volunteers and mCRPC patients using enzalutamide were included to investigate the influence of mCRPC and abiraterone treatment on the circadian rhythm of cortisol. Abiraterone and cortisol levels were measured using validated liquid chromatography-mass spectrometry (LC-MS/MS) assays. Clinical (prostate specific antigen (PSA) independent) PFS and PSA response were evaluated. Results: In total, 117 mCRPC patients using abiraterone acetate, 100 mCRPC patients using enzalutamide and 12 healthy volunteers were included. A clear circadian rhythm of cortisol was described in healthy volunteers and unaffected in mCRPC patients using enzalutamide. Contrarily, a circadian rhythm of cortisol could not be identified in mCRPC patients using abiraterone acetate, due to continuous suppression throughout the day. Patients with an abiraterone Cmin &gt; 8.4 ng/mL (n = 77) had a median cortisol concentration of 1.03 ng/mL vs. 2.59 ng/mL in patients with an abiraterone Cmin ≤8.4 ng/mL (n = 40) (p = 0.020). The median cortisol concentration in PSA responders (n = 63) was 1.02 ng/mL vs. 2.59 ng/mL for PSA non responders (n = 54) (p = 0.037). Patients in the highest cortisol tertile ( &gt; 3.03 ng/mL) had a median PFS of 3.7 months (n = 39) vs. 13.8 months in patients with cortisol levels ≤3.03 ng/mL (n = 78) (p = 0.007). The median PFS was 16.3 months in patients with an abiraterone Cmin &gt; 8.4 ng/mL and cortisol concentration &lt; 3.03 ng/ml vs. 5.3 months in patients with an abiraterone Cmin &gt; 8.4 ng/mL and cortisol concentration &gt; 3.03 ng/ml (p = 0.02). Conclusions: This study demonstrates that cortisol levels are of additional value to abiraterone concentrations as a marker for abiraterone acetate efficacy. This might help be helpful to assess efficacy of abiraterone treatment.

Abiraterone acetate versus bicalutamide in combination with gonadotropin releasing hormone antagonist therapy for high risk metastatic hormone sensitive prostate cancer

The objective of this study was to compare the efficacy of abiraterone acetate with that of bicalutamide in combination with gonadotropin-releasing hormone (GnRH) antagonist treatment for patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). A total of 149 patients with mHSPC who underwent treatment at our hospital and affiliated hospitals between December 2013 and July 2020 were retrospectively identified. Fifty patients were administered abiraterone acetate (1000 mg/day) plus prednisolone (5 mg/day) with a GnRH antagonist (degarelix) (group A), and 99 patients were administered bicalutamide (80 mg/day) with a GnRH antagonist (group B). The prostate-specific antigen (PSA) progression-free survival (PSA-PFS) was significantly longer in group A than in group B. Abiraterone acetate therapy and Gleason score were significant independent factors of PSA-PFS. Using propensity score matching, 56 matched patients were obtained. The PSA-PFS (p < 0.001) and overall survival (OS) (p = 0.0071) of patients with high-risk mHSPC were significantly longer in group A of matched patients. Abiraterone acetate therapy and Gleason score were significant independent factors for PSA-PFS in matched patients. The PSA-PFS and OS of patients treated with abiraterone acetate in combination with a GnRH antagonist were significantly better than those treated with bicalutamide.

Efficacy of abiraterone acetate in castration-resistant metastatic prostate cancer: A real-world data analysis.

The aim of this study was to evaluate the efficacy of abiraterone in patients with castration-resistant metastatic prostate cancer. We retrospectively analyzed 51 patients with mCRPC treated with abiraterone acetate from January 2014 to August 2018. Clinicopathological information, treatment modalities, treatment responses, and survival times were retrospectively reviewed. A total of 51 patients who received abiraterone 1000mg/day + prednisone 10mg/day between January 2014 and August 2018 were included in the study. Of these patients, 33 (64.7%) had post-chemotherapy (CT) and 18 (35.3%) had CT-naive abiraterone receipt. Median overall survival (OS) was 17.3 months (range 9.3-33.1). Median OS was found to be 12.7 months (range 9.4-18.3) and 29.4 months (range 9.3-33.0) in the CT-naive and post-CT group, respectively (P=.236). Median radiographic PFS (rPFS) was 10.1 months (range 4.5-18.4). In the CT-naive group, rPFS was 10.1 months (IQR 6.0-14.7) and in the post-CT group, it was 9.7 months (range 4.0-18.4) (P=.808). PSA progression-free survival (PSA-PFS) was 9.1 months (range 4.6-13.1). In the CT-naive group, PSA-PFS was 7.4 months (range 4.6-13.4) and in post-CT, it was 9.1 months (range 4.8-13.1) (P=.843). These results show that abiraterone acetate is an effective and reliable agent in real-life data.

A quick UPLC-MS/MS method for therapeutic drug monitoring of abiraterone and delta(4)-abiraterone in human plasma.

Abiraterone acetate efficacy against prostate cancer is dependent on the circulating levels of abiraterone and its active metabolites, which present significant pharmacokinetic variability among patients. Thus, therapeutic drug monitoring can be performed to improve treatment outcomes. To support such studies, there are only a limited number of bioanalytical methods in current literature. This work presents a fast method to quantify abiraterone and D4A in plasma in 4 min by UPLC-MS/MS. Bioanalytical method validation was performed according to the recommendations of the US Food and Drug Administration. The method was linear within the range of 1-400 ng/ml for abiraterone and 0.2-20 ng/ml for D4A (r2 > 0.99). Based on the analysis of quality control samples at the lower limit of quantification, low, medium and high concentrations, the method was precise (CVabiraterone ≤ 9.72%; CVD4A ≤ 14.64%) and accurate (CVabiraterone 95.51-107.59%; CVD4A 98.04-99.89%). Application of the method to the quantification of abiraterone and D4A in 10 clinical samples revealed important variability in the conversion ratio of abiraterone to D4A (CV 90.85%). Considering the current literature, this is the fastest method to quantify abiraterone and D4A in plasma, allowing for optimization of the analytical routine.

Abiraterone acetate in combination with prednisone in the treatment of prostate cancer: safety and efficacy

ABSTRACT Introduction Metastatic prostate cancer is a life-threatening disease and an important public health concern with prevalence rates varying drastically between high- and low-income countries. Androgen-deprivation therapy alone has been the first-line treatment option for decades, temporarily controlling disease until invariable tumor regression. At the castration-resistant stage, metastatic disease becomes lethal. In recent years several new treatments, including second-generation hormone therapies, have proven to be life-prolonging in metastatic castration-resistant prostate cancer, and at an earlier hormone-sensitive stage. Abiraterone acetate in combination with prednisone was the first approved hormone therapy demonstrating survival benefit, and represents, to date, an alternative, or a second-line treatment after taxane-based chemotherapy, in addition to androgen-deprivation therapy, in hormone sensitive, and metastatic castration-resistant prostate cancer. Area covered We performed a literature review of papers from 2012 to 2020 using PubMed, Web of Science, and Embase searching for the safety and efficacy of abiraterone acetate in prostate cancer management. Search results were limited to phase III–IV trials and post hoc analysis of Phase III trials evaluated Abiraterone acetate in the English language. Expert opinion This literature review confirms the role of abiraterone acetate in the therapeutic landscape with well-proven safety and efficacy, demonstrated in trials and post-approval studies.

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.

The real-world efficacy of abiraterone acetate (ABA) and docetaxel (DOC) in the treatment of African-American (AA) patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC).

52 Background: The landscape of mCSPC treatment changed with the addition of ABA and DOC. The prevalence of AA pts in the trials that led to these approvals was &lt; 10%. We characterized the clinical outcomes (CO) of a cohort of AA pts treated with these agents. Methods: We retrospectively reviewed 51 AA pts with mCSPC treated with ABA or DOC at Grady Memorial Hospital from 2015-2018. The CO included median overall survival (mOS), progression-free survival (mPFS) and PSA response (PSAr) as defined by a ≥ 50% drop in PSA over the 1st 12 weeks of treatment. Cox proportional hazard model and Kaplan-Meier method were used for association with OS and PFS and logistic regression model for PSAr. Results: Median age was 63 years, 64% were grade group 5 and 67% had an ECOG status of 0-1. 82% had high volume disease per CHAARTED; 51% did per LATITUDE. 21 pts received ABA; 30 received DOC. The groups (ABA vs DOC) were balanced except for high volume disease per LATITUDE (28.6 vs. 66.7%) and lymph node metastases (66.7 vs. 96.7%). The DOC cohort received a mean of 5.2 cycles. Median follow-up was 10.3 months (mos). The overall mOS was 37.8 mos, mPFS was 10.3 mos, and PSAr was 89.6%. CO trended toward favoring ABA over DOC but did not differ significantly with a 12-month OS of 100% vs. 81.7% and PFS of 53.7% vs. 35.4%, respectively. Albumin and hemoglobin at baseline were associated with CO (Table). Conclusions: We present the first real world efficacy of ABA and DOC in a cohort of AA pts with mCSPC and found similar outcomes between the two groups. These findings warrant a larger study for validation.[Table: see text]

A tertiary care audit of using abiraterone acetate in patients of metastatic castrate-resistant prostate cancer.

Introduction:This is a retrospective analysis to assess the safety and efficacy of abiraterone acetate (AA) in metastatic castrate-resistant prostate cancer (mCRPC) patients treated at tertiary care institute.Materials and Methods:The clinical records of mCRPC patients treated with AA at our tertiary care institute between July 2013 and December 2015 were reviewed. The treatment efficacy, toxicities, and its determinants were analyzed.Results:A total of 59 mCRPC patients treated with AA were reviewed, of whom 37 were chemo-naive and 22 had received prior chemotherapy (postchemo). The median follow-up duration was 10.0/15.0 months for chemo-naïve/postchemotherapy patients. 43.2%/36.36% of chemo-naive/postchemo patients had visceral metastases. The median overall survival (OS) and progression-free survival (PFS) were 15/7.8 months and 10/5.3 months for chemo-naive/postchemo patients, respectively. Median time to best prostate-specific antigen response was 3.4 months. Abiraterone was relatively well tolerated with no grade 4 toxicity or treatment-related death. We found the presence of previous taxene use and baseline symptoms to be significantly determinant of OS with abiraterone.Conclusion:The present study reported the efficacy of abiraterone in both chemo-naïve and postchemo patients of mCRPC outside clinical trial setting. We found lower OS and PFS with abiraterone as compared to that reported in the clinical trial setting in both chemo-naïve and postchemo patients, and particularly in those patients with the visceral disease, and further clinical trial for abiraterone in this subgroup of patients is warranted.

Real-world outcome with abiraterone acetate plus prednisone in Asian men with metastatic castrate-resistant prostate cancer: The Singapore experience.

Several small studies have reviewed the efficacy of abiraterone acetate plus prednisolone (AAP) in clinical practice outside a trial setting. We report the largest cohort study of clinical outcomes in metastatic castrate-resistant prostate cancer (mCRPC) patients treated with AAP in a multicenter multiracial clinical setting. A retrospective analysis on mCRPC patients treated at four tertiary hospitals in Singapore from 2012 to 2017 was conducted. Disease characteristics, treatment outcomes, and adverse events were retrieved from electronic medical records. Primary clinical end-point was overall survival (OS). A subset analysis of patients with various variables and OS curves were generated using the Kaplan-Meier method and compared using the log-rank test. Out of 200 patients with mCRPC treated with AAP, 163 (81.5%) patients were chemo-naïve (CN) and 37 (18.5%) patients were postchemotherapy (PC), with the median age of 68 (34-87) and 65 (52-80) years, respectively. Median OS was 20.0 (95% CI, 18.3-22.9) and 10.5 months (95% CI, 1.1-40.5) for CN and PC cohorts, respectively. A subset analysis of 108 patients showed a significantly longer OS in patients who had prior ADT for more than 12 months in CN patients (P < 0.001). Incidences of G3/G4 events were around 6.6%; most common side effect being hypertension with an incidence of 2.4%. Treatment of CN and PC patients with AAP was associated with a comparable OS and progression-free survival to the reported series. Patients who were responsive to prior ADT of 12 months or more were associated with an improved OS.

95P - Evaluation of markers associated with efficacy of abiraterone acetate plus prednisone (AAP) in patients (pts) with castration-sensitive prostate cancer (mCSPC) from the LATITUDE study

BackgroundAAP and androgen deprivation therapy (ADT) treatment significantly improved overall survival (OS) and radiological progression-free survival (rPFS) in mCSPC pts with adverse prognostic factors. This analysis was aimed to identify predictive markers associated with response or resistance to AAP to guide combination and subsequent therapies. MethodsDNA (n=43) and RNA (n=48) extracted from archived tumor samples from the LATITUDE study were sequenced using next generation and targeted DNA sequencing. Androgen receptor (AR) anomalies (copy number changes and mutations), frequency of DNA repair deficient (DRD: BRCA1/2, ATM, BRIP1, CHEK2, PALB2, FANCA, HDAC2) tumors and other resistant markers were probed. ARV7 expression was assessed in archived tumors (n=105) by immunohistochemistry. Associations of biomarkers with rPFS and OS were assessed using univariate cox proportional hazards models. ResultsOf 105 treatment-naïve tumor samples tested, none of them met previously defined H-score cut off for ARV7 staining of>5%, while 4/105 (4%) showed >1% ARV7 staining. A non-synonymous AR mutation (E654K) was detected in one sample (1/43), while none of the samples showed AR amplification. Impact of ARV7 expression on clinical outcomes was inconclusive due to small sample size of positive results. DRD tumors were observed at an overall frequency of 6/42 pts (14.3%: 4 biallelic), 4/30 pts (13.3%; 3 biallelic) in the AAP arm and 2/12 pts (16.7%: 1 biallelic) in control arm. Incidences of BRCA1/2 were only observed in AAP arm at a frequency of 2/30 (6.7%). In the AAP arm, shorter PFS was observed for DRD+ vs DRD– cohort (median 21.01 vs 24.14mo; HR: 3.9; 95% CI: 1.1-12.1; p=0.03). Genomic alterations were observed in PTEN (32.5%), TMPRSS2 (30%), TP53 (25.55), SPOP (20.9%) and APC (13.9%) genes, however, associations with clinical outcomes were not meaningful due to fewer samples and events. ConclusionsAR splice variants and mutations were absent/rare in treatment naïve tumor samples from men with castrate-sensitive prostate cancers. The DRD+ cohort appears to show poorer rPFS outcome in AAP treated men. Clinical trial identificationNCT01715285. Editorial acknowledgementShweta Pitre, MPharm, ISMPP CMPP™ (SIRO Clinpharm Pvt. Ltd., India) provided writing assistance and Namit Ghildyal, PhD (Janssen Global Services, LLC) provided additional editorial support. Legal entity responsible for the studyJanssen Research and Development, LLC. FundingJanssen Research and Development, LLC. DisclosureK.N. Chi: Research grant/Funding (self): Janssen Pharmaceuticals, Astellas Pharma, Amgen, Bayer, Novartis, Sanofi, Exelixis, Tokai Pharmaceuticals, Oncogenex, Teva; Advisory/Consultancy: ESSA, Astellas Pharma, Janssen Pharmaceuticals, Sanofi, Lilly/ImClone, Amgen, Bayer, Takeda Pharmaceuticals; Honoraria (self): Sanofi, Janssen Pharmaceuticals, Astellas Pharma. S. Thomas: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. M. Gormley: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. D. Shen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. S. Joshi: Full/Part-time employment: Janssen Research & Development. N. Tran: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. M. Smith: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. D. Ricci: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. K. Fizazi: Advisory/Consultancy, Received personal fees: Amgen; Advisory/Consultancy, Received personal fees: Astellas; Advisory/Consultancy, Received personal fees: AstraZeneca; Advisory/Consultancy, Received personal fees: Bayer; Advisory/Consultancy, Received personal fees: Clovis; Advisory/Consultancy, Received personal fees: Curevac; Advisory / Consultancy, Received personal fees: Essa; Advisory/Consultancy, Received personal fees: Genentech; Advisory/Consultancy, Received personal fees: Janssen; Advisory/Consultancy, Received personal fees: Merck Sharp and Dohme; Advisory/Consultancy, Received personal fees: Orion; Advisory/Consultancy, Received personal fees: Sanofi.

Going towards a precise definition of the therapeutic management of de-novo metastatic castration sensitive prostate cancer patients: How prognostic classification impact treatment decisions

De-novo metastatic castration sensitive prostate cancer (mCSPC) is a subgroup of prostate cancer associated with poor prognosis. Recently, the treatment of mCSPC has been enriched by new life-prolonging options, including the combination of docetaxel or abiraterone acetate with androgen deprivation therapy (ADT). Of note, the advantage of chemohormonal therapy was more relevant in the subgroup of high-volume disease compared to low-volume, while the survival prolongation of abiraterone was observed only in high-risk patients. Choosing the most appropriate therapy is one of the most debated issues. This review describes the latest news on de-novo mCSPC to better outline patients' management. At the ESMO 2018 Congress two novel studies focused on this setting have been presented, trying to define the role of radiotherapy to the primary tumour and the efficacy of abiraterone acetate in the subset of low-risk patients. We have analysed these results in light of the evidence already available.

Abstract P2-06-04: Enhancing abiraterone acetate efficacy in androgen receptor-positive triple negative breast cancer: Chk1 as a potential target

Abstract Purpose: Our aim was to identify predictive factors of abiraterone acetate (AA) efficacy and putative new druggable targets in androgen receptor (AR)-positive triple-negative breast cancer (TNBC) treated in the UCBG 2012-1 trial. Material and methods: We defined AA response as either complete or partial response, or stable disease at 6 months. Using Ampliseq, we sequenced 91 general and breast cancerassociated genes from the tumor DNA samples. We analyzed transcriptomes from the extracted RNA samples on a Nanostring platform and performed immunohistochemistry (IHC) on tumor samples using tissue microarrays. We assessed AA and CHK1 inhibitors (GDC-0575 and AZD7762) efficacies, either alone or in combination, on cell lines grown in vitro and in vivo. Results: Classical IHC apocrine markers, including AR, FOXA1, GGT1 and GCDFP15, allowed identifying AA responders and non-responders. All responders have clear apocrine features. Transcriptome analysis revealed that 31 genes were differentially expressed in the two subgroups, 9 of them being linked to proliferation and DNA damage repair. One of the most significant differences was the overexpression in non-responders of CHEK1, a gene encoding Chk1, a protein kinase that can be blocked by specific inhibitors. In vitro, AA and Chk1 inhibitor combination showed additive or slightly synergistic effect on cell viability, cell cycle, apoptosis and accumulation of DNA damages. In vivo, orthotopic xenograft experiments confirmed the efficacy of this combination therapy. Conclusions: This study suggests that apocrine features can be helpful in the identification of AA-responders. We identified Chk1 as a putative drug target in AR-positive TNBCs. Citation Format: Grellety T, Callens C, Richard E, Pulido M, Goncalves A, Gestraud P, MacGrogan G, Bonnefoi H, Cardinaud B. Enhancing abiraterone acetate efficacy in androgen receptor-positive triple negative breast cancer: Chk1 as a potential target [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-04.

Enhancing Abiraterone Acetate Efficacy in Androgen Receptor-positive Triple-negative Breast Cancer: Chk1 as a Potential Target.

Our aim was to identify predictive factors of abiraterone acetate efficacy and putative new druggable targets in androgen receptor (AR)-positive triple-negative breast cancer (TNBC) treated in the UCBG 2012-1 trial.Experimental Design: We defined abiraterone acetate response as either complete or partial response, or stable disease at 6 months. We sequenced 91 general and breast cancer-associated genes from the tumor DNA samples. We analyzed transcriptomes from the extracted RNA samples on a NanoString platform and performed IHC using tissue microarrays. We assessed abiraterone acetate and Chk1 inhibitors (GDC-0575 and AZD7762) efficacies, either alone or in combination, on cell lines grown in vitro and in vivo. Classic IHC apocrine markers including AR, FOXA1, GGT1, and GCDFP15, from patients' tumors allowed identifying abiraterone acetate-responders and nonresponders. All responders had clear apocrine features. Transcriptome analysis revealed that 31 genes were differentially expressed in the two subgroups, 9 of them being linked to proliferation and DNA damage repair. One of the most significant differences was the overexpression, in nonresponders, of CHEK1, a gene encoding Chk1, a protein kinase that can be blocked by specific inhibitors. On the basis of cell line experiments, abiraterone acetate and Chk1 inhibitor combination showed at least additive effect on cell viability, cell cycle, apoptosis, and accumulation of DNA damages. In vivo, orthotopic xenograft experiments confirmed the efficacy of this combination therapy. This study suggests that apocrine features can be helpful in the identification of abiraterone acetate-responders. We identified Chk1 as a putative drug target in AR-positive TNBCs.

P049 - Efficacy of Abiraterone acetate plus Prednisone and Enzalutamide sequences in men with metastatic castration-resistant prostate cancer: Systematic review and meta-analysis

P049 - Efficacy of Abiraterone acetate plus Prednisone and Enzalutamide sequences in men with metastatic castration-resistant prostate cancer: Systematic review and meta-analysis