Association of body composition with survival and efficacy of first-line treatment in patients with castration-resistant prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 115-115
Author(s):  
Jae Young Joung ◽  
Sahyun Pak

115 Background: We aimed to investigate the association of body composition with survival and efficacy of first-line treatments in patients with castration-resistant prostate cancer (CRPC). Methods: Records of CRPC patients who were treated with first-line docetaxel or androgen receptor signaling inhibitors (ARSi) between 2005 and 2018 were reviewed. Skeletal muscle index (SMI), visceral fat index, and subcutaneous fat index were evaluated using pretreatment computed tomography images. Results: Of the 230 eligible patients, 144 patients received docetaxel and 86 received ARSi as the first-line treatment for CRPC. SMIhi (based on median value) group had higher prostate-specific antigen (PSA) progression-free survival (median 13.5 vs. 8.3 months, p=0.030), radiologic progression-free survival (14.9 vs. 9.1 months; p<0.001), and overall survival (24.1 vs. 16.9 months, p=0.015) compared than SMIlo group. In multivariable analysis, SMI was independently associated with risk of PSA progression (HR=0.68; 95% CI, 0.50-0.93; p=0.017), radiologic progression (HR=0.54; 95% CI, 0.39-0.75; p=0.001), and overall survival (HR=0.72; 95% CI, 0.52-0.98; p=0.037), regardless of BMI. In docetaxel-treated patients, PSA progression-free survival (13.5 vs. 5.9 months, p=0.016) and radiologic progression-free survival (14.6 vs. 6.7 months, p<0.001) were higher in SMIhi than SMIlo group. However, PSA progression-free survival and radiologic progression-free survival were similar between two groups in ARSi-treated patients. Based on treatment-specific hazards of radiologic progression, patients with SMIlo are more likely to benefit from ARSi compared than docetaxel. Conclusions: High skeletal muscle mass may be associated with reduced risks of disease progression and mortality in patients with CRPC. However, the significance of these relationships is limited in patients treated with docetaxel. These results suggest that skeletal muscle mass may be helpful in treatment selection and predicting treatment response in CRPC. Further prospective studies are warranted.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 133-133
Author(s):  
Yuchao Ni ◽  
Jinge Zhao ◽  
Junru Chen ◽  
Guangxi Sun ◽  
Sha Zhu ◽  
...  

133 Background: Abiraterone is the first-line treatment for men with metastatic castration-resistant prostate cancer (mCRPC) and is recommended to be used with prednisone. Previous studies had demonstrated that the switch from prednisone to dexamethasone in some mCRPC patients can reverse abiraterone-resistance. However, it remains uncertain which group of patients will benefit from such switching. AKR1C3 is a critical enzyme contributing to the drug-resistance of abiraterone. Here, we aim to explore the significance of AKR1C3 in predicting the therapeutic efficacy of the corticosteroid switching in mCRPC patients receiving abiraterone. Methods: In total, 43 PCa patients treated with abiraterone after mCRPC between 2016 and 2018 in our institution were included. After biochemical progression in abiraterone plus prednisone, all cases received a corticosteroid switch to abiraterone plus dexamethasone. The expression of AKR1C3 was detected by immunohistochemical staining from re-biopsy (re‐Bx) of primary prostate lesions at the time of mCRPC. Kaplan‐Meier curves were used to analyze the association between AKR1C3 and treatment outcomes. Results: Totally, AKR1C3 was positive in 19 of 43 (44.19%) cases. In the corticosteroid switch treatment, 30% PSA decline was confirmed in 18/43 (41.86%) patients, while the median PSA progression‐free survival (PSA-PFS) and overall survival (OS) was 4.93 Mo and 31.57 Mo, respectively in the whole cohort. AKR1C3 expression was associated with statistically shorter median PSA-PFS (4.50 Mo vs 7.73 Mo; p =0.010) and numerically lower median OS (25.43 Mo vs 39.37 Mo, p =0.274). While the 30% PSA decline rate was numerically comparable between those with and without AKR1C3 expression (31.6% vs 50.0%, p =0.224). Conclusions: This study showed AKR1C3 detection in tissues from prostate re‐Bx at mCRPC was associated with poor PSA-PFS in the corticosteroid switch from abiraterone plus prednisone to abiraterone plus dexamethasone. These results would be helpful in making optimal personalized treatment decisions for patients with mCRPC, facilitating physicians predicting the effectiveness of corticosteroid switch treatment.


2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 242-242
Author(s):  
Wataru Fukuokaya ◽  
Takahiro Kimura ◽  
Fumihiko Urabe ◽  
Shoji Kimura ◽  
Kojiro Tashiro ◽  
...  

242 Background: In the present guidelines for the management of metastatic castration-resistant prostate cancer (CRPC), it is unclear who benefits from androgen receptor axis-targeted agents (ARATs) or docetaxel as a first-line treatment. Methods: We conducted a single-institutional retrospective study to explore treatment-specific biomarkers for treatment response of metastatic CRPC. A cohort of 211 patients with metastatic CRPC treated with either ARAT (abiraterone acetate or enzalutamide) or docetaxel as a first-line treatment was evaluated. In addition to well-established biomarkers such as hemoglobin, neutrophil-to-lymphocyte ratio, alkaline phosphatase, and lactate dehydrogenase, we also assessed red cell distribution width, platelet count, and mean platelet volume (MPV). Laboratory measures were assessed within 1 month before starting treatment. Prostate-specific antigen progression-free survival (PSA-PFS) and radiographic progression-free survival (RPFS) were evaluated. Multivariable Cox regression models were used to assess the association between biomarkers and the risk of events. We also studied the statistical interaction between biomarkers and clinical outcomes. Results: Of all blood-based biomarkers, multivariable Cox regression models identified pre-treatment MPV (≤9.0 fL) as an independent prognostic factor of both PSA progression (hazard ratio [HR]: 2.62, 95% confidence interval [CI]: 1.25-5.48, P = 0.011) and radiographic progression (HR: 4.46, 95% CI: 1.79-11.1, P = 0.001). In addition, these models showed a lower risk of PSA progression (HR: 0.38, 95% CI: 0.15-0.96, P = 0.041) and radiographic progression (HR: 0.16, 95% CI: 0.05-0.50, P = 0.002) with docetaxel compared with ARAT when pre-treatment MPV was small. Conclusions: The present study identified MPV as a significant treatment-specific prognostic factor of PSA progression and radiographic progression in patients with metastatic CRPC treated with a first-line treatment. Furthermore, our results suggested that small MPV was associated with superior survival benefit on docetaxel over ARAT.


Author(s):  
Mikifumi Koura ◽  
Masaki Shiota ◽  
Shohei Ueda ◽  
Takashi Matsumoto ◽  
Satoshi Kobayashi ◽  
...  

Abstract Objective This study aimed to reveal the prognostic values of prior local therapy in first-line therapy using androgen receptor-axis targeting agents (abiraterone or enzalutamide) or docetaxel for castration-resistant prostate cancer (CRPC). Methods The study included 303 patients treated with first-line therapy for non-metastatic and metastatic CRPC. The association between prior local therapy and therapeutic outcome including progression-free survival and overall survival was investigated by univariate and multivariate analyses as well as propensity score-matched analysis. Results In univariate analysis, local prior therapy was associated with a lower risk of all-cause mortality (hazard ratio, 0.56, 95% confidence interval, 0.40–0.79; P = 0.0009). Overall survival, but not progression-free survival, was better among patients with prior local therapy compared with patients without prior local therapy even after multivariate analysis and propensity score-matched analysis. Conclusions This study robustly indicated that prior local treatment was prognostic for overall survival among patients with CRPC. This finding is useful to predict patient prognosis in CRPC.


2017 ◽  
Vol 35 (19) ◽  
pp. 2149-2156 ◽  
Author(s):  
Emmanuel S. Antonarakis ◽  
Changxue Lu ◽  
Brandon Luber ◽  
Hao Wang ◽  
Yan Chen ◽  
...  

Purpose We reported previously that the detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumor cells (CTCs) correlated with poor outcomes from the use of abiraterone and enzalutamide in patients with castration-resistant prostate cancer (CRPC). Here, we expanded our cohort size to better characterize the prognostic significance of AR-V7 in this setting. Methods We prospectively enrolled 202 patients with CRPC starting abiraterone or enzalutamide and investigated the prognostic value of CTC detection (+ v –) and AR-V7 detection (+ v –) using a CTC-based AR-V7 mRNA assay. We examined ≥ 50% prostate-specific antigen (PSA) responses, PSA progression-free survival, clinical and radiologic progression-free survival, and overall survival. We constructed multivariable models adjusting for PSA, Gleason sum, number of prior hormone therapies, prior abiraterone or enzalutamide use, prior taxane use, presence of visceral metastases, and Eastern Cooperative Oncology Group score. We also separately examined the first-line and second-line novel hormonal therapy (NHT) settings. Results Median follow-up times were 15.0, 21.7, and 14.6 months for CTC–, CTC+/AR-V7– and CTC+/AR-V7+ patients, respectively. CTC+/AR-V7+ patients were more likely to have Gleason scores ≥ 8 ( P = .05), metastatic disease at diagnosis ( P = .01), higher PSA ( P < .01), prior abiraterone or enzalutamide use ( P = .03), prior taxane use ( P = .02), and Eastern Cooperative Oncology Group ≥ 1 ( P = .01). Outcomes for the overall cohort (and separately for the first-line and second-line NHT cohorts) were best for CTC– patients, intermediate for CTC+/AR-V7– patients, and worse for CTC+/AR-V7+ patients. These correlations remained significant in multivariable models. Conclusion This expanded analysis further characterizes the importance of CTC-based AR-V7 mRNA detection in predicting outcomes in patients with CRPC receiving first- and second-line NHT and, to the best of our knowledge, is the first to suggest that this assay be interpreted using three separate prognostic categories: CTC–, CTC+/AR-V7–, and CTC+/AR-V7+.


2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 132-132 ◽  
Author(s):  
John Silberstein ◽  
Brandon Luber ◽  
Hao Wang ◽  
Changxue Lu ◽  
Yan Chen ◽  
...  

132 Background: AR-targeting agents remain the backbone of mCRPC therapy. We previously reported an association between AR-V7 mRNA detection in CTCs and resistance to Abi/Enza (NEJM 2014). Here, we report the prognostic significance of full-length androgen receptor (AR-FL) mRNA quantification from CTCs in pts starting Abi or Enza. Methods: We prospectively enrolled mCRPC pts starting Abi or Enza, and examined the prognostic value of AR-FL detection using a CTC-based mRNA assay (modified AdnaTest, Qiagen). We examined PSA50 responses, PSA progression free survival (PSA-PFS), clinical/radiologic PFS (PFS), and overall survival (OS). We constructed multivariable (MVA) Cox regression models adjusting for AR-V7 status, PSA level, Gleason sum, number of prior therapies, prior Abi/Enza use, prior taxane use, presence of visceral disease, and ECOG score. Results: We enrolled 202 pts (median f/u 12.9 mo). AR-FL status was negative in 97/202 pts (48%), < median in 52/202 (26%) and > median in 53/202 (26%). Higher AR-FL levels correlated with positive AR-V7 detection (35.5 copies [range: 2.5–1209] in AR-V7+ vs 1.4 copies [range: 0–172.5] in AR-V7–, P< .001), as well as lower PSA50 responses (55.4 copies in nonresponders vs 6.7 copies in responders, P< .001). In Kaplan-Meier analysis, PSA-PFS, PFS and OS differed significantly between AR-FL negative, AR-FL < median, and AR-FL > median (Table). In MVA models, AR-FL level (as a continuous variable) was prognostic for PSA-PFS (HR 1.06, 95%CI 1.00–1.12, P= .04) and trended with prognosis for PFS (HR 1.04, 95%CI 0.99–1.11, P= .13) and OS (HR 1.07, 95%CI 1.00–1.15, P= .06). AR-V7 status was also independently prognostic for all outcomes in MVA analyses. Conclusions: This study demonstrates CTC-derived AR-FL copy number is prognostic for clinical outcomes in Abi/Enza-treated mCRPC pts. In addition to AR-V7 status, AR-FL quantification could serve as another molecular biomarker of Abi/Enza sensitivity after analytical validation/standardization. [Table: see text]


2020 ◽  
Author(s):  
Zhipeng Wang ◽  
Sha Zhu ◽  
Jinge Zhao ◽  
Ling Nie ◽  
Xueqin Chen ◽  
...  

Abstract BackgroundTo explore whether patients with distinct intraductal carcinoma of the prostate (IDC-P) subtypes respond differently to standard first-line therapy among patients with metastatic castration resistant prostate cancer (mCRPC).MethodsWe retrospectively analyzed data of 170 mCRPC patients receiving abiraterone (ABI) or docetaxel (DOC) as first-line therapy between 2014 and 2019. PSA response, PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS) were analyzed and compared based on the presence of IDC-P and its sub-patterns.ResultsTotally, IDC-P was confirmed in 91/170 (53.5%) patients. Among them, 36/91 (39.6%) and 55/91 (60.4%) harbored IDC-P pattern 1 and pattern 2, respectively. The presence of IDC-P was confirmed to be associated with poor prognosis in the whole cohort. Patients with IDC-P pattern 1 shared similar clinical outcomes to those without IDC-P in both ABI and DOC treatment. However, compared to patients with IDC-P pattern 1 and without IDC-P, IDC-P pattern 2 had markedly poorer prognosis in either ABI (PSA-PFS: P<0.001; rPFS: P<0.001) or DOC (PSA-PFS: P<0.001; rPFS: P<0.001) treatment. For patients without IDC-P, DOC had comparable therapeutic efficacy with ABI. In contrast, the therapeutic efficacy of DOC in patients with either IDCP pattern 1 (PSA-PFS: P=0.021; rPFS: P=0.027) or pattern 2 (PSA-PFS: P=0.003; rPFS: P=0.007) was significantly inferior to ABI.ConclusionCompared to DOC, ABI exhibited better efficacy in patients with IDC-P of either pattern. However, IDC-P pattern 2 still responded unsatisfactorily to either ABI or DOC therapy. Novel therapeutic strategies appropriate for IDC-P pattern 2 need to be further investigated in the future.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5005-5005 ◽  
Author(s):  
Mary-Ellen Taplin ◽  
Emmanuel S. Antonarakis ◽  
Karen J. Ferrante ◽  
Kerry Horgan ◽  
Brent A. Blumenstein ◽  
...  

5005 Background: Presence of the AR-V7 splice variant may predict resistance to Enz and abiraterone in men with mCRPC. Gal is an oral agent that disrupts AR signaling via AR degradation, CYP17 lyase inhibition, and AR antagonism. ARMOR3-SV was designed to test the hypothesis that in mCRPC patients with AR-V7+ CTCs, Gal could improve radiographic progression-free survival (rPFS) versus Enz. Methods: In this randomized, open-label, multicenter phase 3 study (NCT02438007), men with treatment-naïve mCRPC were screened for CTC-specific AR-V7 (Qiagen), and AR-V7+ men were randomized 1:1 to Gal or Enz. rPFS (by independent blinded central review) was the primary endpoint. Planned sample size was 148, with 120 rPFS events to achieve 90% power to detect a hazard ratio of ≤0.55. Results: 953 patients were screened globally for AR-V7 from Sept 2015 through study closure; 73 men (8%; 95% CI 6-10%) were AR-V7+, 250 (26%) AR-V7–, and 630 (66%) had no CTCs/AR present (unevaluable). AR-V7 detection was associated with higher PSA levels ( > vs < median; P < 0.01), more bone metastases ( > 20 vs 11-20 vs 6-10 vs 0-5; P < 0.01), presence of M1 disease at diagnosis (dx) (yes vs no; P = 0.04), shorter time from dx to screening ( < vs > median; P < 0.01), higher ECOG (≥1 vs 0; P = 0.02), prior antiandrogen use (yes vs no; P < 0.01) and prior docetaxel use (yes vs no; P < 0.01). Among the AR-V7+ men, 38 were randomized (19 Gal, 19 Enz), 31 screen failed, and 4 were discontinued from screening at study halt. Baseline characteristics were balanced. On the recommendation of the DSMB, the study was closed early as it was unlikely to meet its primary endpoint. At the time of the study closure, in the Gal and Enz arms respectively, median time on therapy was 2.0 vs 2.8 mo, median time to PSA progression (PCWG1) was 3.9 vs 3.8 mo, PSA50 response rates in evaluable patients were 2/16 (13%) and 8/19 (42%), and there were no new safety signals. Conclusions: In treatment-naïve mCRPC patients, AR-V7 detection is more common in men with higher disease burden and portends a poor prognosis. Novel study designs and alternative treatment approaches are urgently needed for AR-V7+ mCRPC patients. Clinical trial information: NCT02438007.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5570-5570
Author(s):  
Marine Gross-Goupil ◽  
Nicolas H. Thurin ◽  
Magali Rouyer ◽  
Jérémy Jové ◽  
Thibaud Haaser ◽  
...  

5570 Background: Therapeutic strategy in metastatic castration-resistant prostate cancer (mCRPC) has evolved significantly with the introduction of abiraterone acetate in association with prednisone/prednisolone in first-line treatment in December 2012. This work aimed to compare the effectiveness of abiraterone acetate and docetaxel as first-line treatments for mCRPC, in real-life setting. Methods: Patients with mCRPC were identified in the main scheme of the National Healthcare System database (SNDS), which covers about 86% of the French population, and capturing all reimbursed healthcare expenditures and hospital discharge summaries. Those initiating docetaxel or abiraterone acetate in 1st line in 2014 were included and 1:1 matched on the previous prostate cancer stage before mCRPC status, the delay from the date of initial diagnosis and a high-dimensional propensity score. The 36-month overall survival and the 36-month discontinuation-free survival (i.e. survival time until treatment switch or death) were compared using Cox proportional hazards risk model. Results: In 2014, out of the 12,951 patients with prevalent mCRPC, 1,214 initiated docetaxel in 1st line and 2 444 initiated abiraterone. A total of 716 patients per group were matched with good comparability (C-statistic = 0.6). The median duration of docetaxel–defined as the time between the first and the last infusion–was 7.3 months with a median of 6 infusions. The median duration of abiraterone acetate–corresponding to the period covered by the dispensed drug–was 9.1 months. Near 70% of the docetaxel and 62% of the abiraterone acetate patients received a 2nd line of treatment. Results related to the main survival outcomes are presented in the table below. Conclusions: First-line treatment with abiraterone acetate in mCRPC patients results in a better 36-month overall survival and discontinuation-free survival compared to docetaxel in real-life setting. [Table: see text]


2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Mike Fang ◽  
Mary Nakazawa ◽  
Emmanuel S. Antonarakis ◽  
Chun Li

We examined the comparative efficacies of first-line abiraterone and enzalutamide in pre- and postdocetaxel settings in castration-resistant prostate cancer (CRPC) through a trial level meta-analysis. A mixed method approach was applied to 19 unique studies containing 17 median overall survival (OS) estimates and 13 median radiographic progression-free survival (PFS) estimates. We employed a random-effects meta-analysis to compare efficacies of abiraterone and enzalutamide with respect to OS and PFS. In the predocetaxel setting, enzalutamide use was associated with an increase in median OS of 5.9 months (p<0.001), hazard ratio (HR) = 0.81, and an increase in median PFS of 8.3 months (p<0.001), HR = 0.47 compared to abiraterone. The advantage of enzalutamide improved after adjusting for baseline Gleason score to 19.5 months (p<0.001) and 14.6 months (p<0.001) in median OS and PFS, respectively. In the postdocetaxel setting, the advantage of enzalutamide use was nominally significant for median PFS (1.2 months p=0.02 without adjustment and 2.2 months and p=0.0007 after adjustment); there was no significant difference in median OS between the two agents. The results from this comprehensive meta-analysis suggest a survival advantage with the use of first-line enzalutamide over abiraterone in CRPC and highlight the need for prospective clinical trials.


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