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Plasma cell-free DNA-based predictors of response to abiraterone acetate/prednisone and prognostic factors in metastatic castration-resistant prostate cancer.

ABSTRACT: BACKGROUND:The combination of abiraterone acetate and prednisone (AA/P) is used to treat metastatic prostate cancer, but molecular predictors of treatment response are not well elucidated. We evaluated plasma circulating tumor DNA- (ctDNA-) based copy number alterations (CNAs) to determine treatment-related predictive and prognostic biomarkers for metastatic castration-resistant prostate cancer (mCRPC). METHODS:Serial plasma specimens were prospectively collected from 88 chemotherapy-naive mCRPC patients before and after 12 weeks of AA/P treatment. Sequencing-based CNA analyses were performed on 174 specimens. We evaluated CNA-associated 12-week responses for primary resistance, time to treatment change (TTTC) for secondary resistance, and overall survival for prognosis (P?

SUBMITTER: Du M

PROVIDER: S-EPMC7501185 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Plasma cell-free DNA-based predictors of response to abiraterone acetate/prednisone and prognostic factors in metastatic castration-resistant prostate cancer.

Du Meijun M Tian Yijun Y Tan Winston W Wang Liewei L Wang Liguo L Kilari Deepak D Huang Chiang-Ching CC Wang Liang L Kohli Manish M

Prostate cancer and prostatic diseases 20200318 4

<h4>Background</h4>The combination of abiraterone acetate and prednisone (AA/P) is used to treat metastatic prostate cancer, but molecular predictors of treatment response are not well elucidated. We evaluated plasma circulating tumor DNA- (ctDNA-) based copy number alterations (CNAs) to determine treatment-related predictive and prognostic biomarkers for metastatic castration-resistant prostate cancer (mCRPC).<h4>Methods</h4>Serial plasma specimens were prospectively collected from 88 chemother ...[more]

PMID: 32203070

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Project description:PurposeMetastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies. Homologous recombination repair (HRR) gene alterations, including BRCA1/2 alterations, can sensitize cancer cells to poly (ADP-ribose) polymerase inhibition, which may improve outcomes in treatment-naïve mCRPC when combined with androgen receptor signaling inhibition.MethodsMAGNITUDE (ClinicalTrials.gov identifier: NCT03748641) is a phase III, randomized, double-blinded study that evaluates niraparib and abiraterone acetate plus prednisone (niraparib + AAP) in patients with (HRR+, n = 423) or without (HRR-, n = 247) HRR-associated gene alterations, as prospectively determined by tissue/plasma-based assays. Patients were assigned 1:1 to receive niraparib + AAP or placebo + AAP. The primary end point, radiographic progression-free survival (rPFS) assessed by central review, was evaluated first in the BRCA1/2 subgroup and then in the full HRR+ cohort, with secondary end points analyzed for the full HRR+ cohort if rPFS was statistically significant. A futility analysis was preplanned in the HRR- cohort.ResultsMedian rPFS in the BRCA1/2 subgroup was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.6 v 10.9 months; hazard ratio [HR], 0.53; 95% CI, 0.36 to 0.79; P = .001). In the overall HRR+ cohort, rPFS was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.5 v 13.7 months; HR, 0.73; 95% CI, 0.56 to 0.96; P = .022). These findings were supported by improvement in the secondary end points of time to symptomatic progression and time to initiation of cytotoxic chemotherapy. In the HRR- cohort, futility was declared per the prespecified criteria. Treatment with niraparib + AAP was tolerable, with anemia and hypertension as the most reported grade ≥ 3 adverse events.ConclusionCombination treatment with niraparib + AAP significantly lengthened rPFS in patients with HRR+ mCRPC compared with standard-of-care AAP.[Media: see text].

Project description:IntroductionProstate cancer (PC) is the second leading cause of cancer death among US men and accounts for considerable healthcare expenditures. We evaluated economic outcomes in men with chemotherapy-naïve metastatic castration-resistant PC (mCRPC) treated with enzalutamide or abiraterone acetate plus prednisone (abiraterone).MethodsWe performed a retrospective analysis on 3174 men (18 years or older) utilizing the Veterans Health Administration (VHA) database from 1 April 2014 to 31 March 2018. Men with mCRPC were included if they had at least one pharmacy claim for enzalutamide or abiraterone (first claim date = index date) following surgical or medical castration, had no chemotherapy treatment within 12 months prior to the index date, and had continuous VHA enrollment for at least 12 months pre- and post-index date. Men were followed until death, disenrollment, or end of study and were 1:1 propensity score matched (PSM). All-cause and PC-related resource use and costs per patient per month (PPPM) in the 12 months post index were compared between matched cohorts.ResultsWe identified 1229 men with mCRPC prescribed enzalutamide and 1945 prescribed abiraterone with mean ages of 74 and 73 years, respectively. After PSM, each cohort had 1160 patients. The enzalutamide cohort had fewer all-cause (2.51 vs 2.86; p < 0.0001) and PC-related outpatient visits (0.86 vs 1.03; p < 0.0001), with corresponding lower all-cause ($2588 vs $3115; p < 0.0001) and PC-related ($1356 vs $1775; p < 0.0001) PPPM outpatient costs compared with the abiraterone cohort. All-cause total costs (medical and pharmacy) PPPM ($8085 vs $9092; p = 0.0002) and PC-related total costs PPPM ($6321 vs $7280; p < 0.0001) were significantly lower in the enzalutamide cohort compared with the abiraterone cohort.ConclusionsEnzalutamide-treated men with chemotherapy-naïve mCRPC had significantly lower resource utilization and healthcare costs compared with abiraterone-treated men.

Project description:ObjectiveRecently, hormonal therapy using abiraterone acetate, a second-generation androgen receptor axis-targeted agent, was reported to improve overall survival and progression-free survival in men with LATITUDE-high-risk metastatic castration-sensitive prostate cancer. This observational multicenter study aimed to assess the efficacy of upfront abiraterone acetate in Japanese patients with LATITUDE-high-risk metastatic castration-sensitive prostate cancer.MethodsThe present study included 112 Japanese patients with LATITUDE-high-risk metastatic castration-sensitive prostate cancer who received upfront abiraterone acetate at four institutions belonging to the Tokai Urologic Oncology Research Seminar group, between January 2018 and September 2020. Progression-free survival and overall survival were assessed, and Cox regression analyses were carried out to evaluate the prognostic significance of upfront abiraterone acetate for progression-free survival.ResultsWithin a median follow-up period of 13 months, the progression-free survival and overall survival rates were 76.8% and 89.3%, respectively. Both univariate and multivariable Cox regression analyses showed that the presence of Gleason pattern 5, performance status and hemoglobin were independent predictors of progression-free survival. The patients were subsequently divided into three groups as follows: group 1, 17 patients negative for these three independent progression-free survival predictors; group 2, 49 patients with one positive independent progression-free survival predictor; and group 3, 45 patients with two or three independent progression-free survival predictors. Progression-free survival was significantly different among these three groups (P < 0.001).ConclusionUpfront abiraterone acetate might provide satisfactory outcomes for Japanese patients with LATITUDE-high-risk metastatic castration-sensitive prostate cancer. Gleason pattern 5, performance status and hemoglobin are potential predictors of progression-free survival in Japanese patients with LATITUDE-high-risk metastatic castration-sensitive prostate cancer who received upfront abiraterone acetate.

Dataset Information

Plasma cell-free DNA-based predictors of response to abiraterone acetate/prednisone and prognostic factors in metastatic castration-resistant prostate cancer.

Publications

Plasma cell-free DNA-based predictors of response to abiraterone acetate/prednisone and prognostic factors in metastatic castration-resistant prostate cancer.

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