Prognostication of outcome in men with bone metastatic castration-resistant-prostate-cancer with early rising PSA after initiation of abiraterone acetate.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16514-e16514
Author(s):  
Martin Boegemann ◽  
Phillip Grossmann ◽  
Julie Steinestel ◽  
Katrin Schlack ◽  
Laura Maria Krabbe ◽  
...  

e16514 Background: Abiraterone acetate (AA) prolongs survival in men with mCRPC in the pre- and post chemotherapy setting and is mainly used in asymptomatic men. In the first 12 weeks an early rise of prostate specific antigen (PSA) may occur followed by either delayed decline (PSA-flare) or true progression. Bouncing of alkaline phosphatase (ALP-Bouncing) was shown to be a promising marker for outcome and response during very early AA therapy. This retrospective study was conducted to analyze the capability of ALP-Bouncing to predict overall survival (OS) in men with bone mCRPC (bmCRPC) with rising PSA after initiation of AA therapy. Methods: Men with bmCRPC and rising PSA during early AA therapy were includeded and analyzed. PSA response rate (RR) was monitored according to PCWG2 criteria and assessed 12 weeks after start of AA treatment. PSA-flare vs. no flare and ALP-Bouncing vs. no Bouncing were analyzed using Kaplan-Meyer estimates and uni- and multivariate (UV/MV) cox-regression models. ALP-Bouncing was defined as increase of ALP after the beginning of AA with a subsequent significant decline below baseline during the first 8 weeks of therapy. Results: Forty men were evaluable for analysis: 20 men were chemotherapy naïve, 20 pretreated with docetaxel. The PSA RR was 30%. The median survival for ALP-Bouncing was 20 months (95% confidence interval (95%CI): 4.7-13.3) vs. 9 months (95%CI not distinguishable) for no ALP-bouncing (p = 0.04) and 13 months (95%CI: 8.8-17.2) for PSA-flare vs. 9 months (95%CI 4.4-13-6) for no PSA-flare (p = 0.62). In UV no ALP-bouncing was significantly associated with worse OS (Hazard Ratio (HR): 2.65 (95%CI: 1.0-7.0); p = 0.05). After adjustment for PSA-flare no AP-bouncing remained an independent prognosticator of worse OS (HR: 2.78 (95%CI: 1.0-7.71); p = 0.05). Conclusions: ALP-Bouncing, occurring earlier than delayed PSA-decline, may be a helpful marker to identify patients with subsequent favorable outcome in men with bmCRPC and rising PSA after initiation of AA therapy. These results have to be validated in a prospective trial.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 99-99 ◽  
Author(s):  
Bo Zhao ◽  
Jorge A. Garcia ◽  
Timothy D. Gilligan ◽  
Brian I. Rini ◽  
Robert Dreicer

99 Background: Studies have shown activity of Abiraterone acetate (AA) in patients (pts) with castration-resistant prostate cancer (CRPC) who have received prior ketoconazole. Prostate-specific antigen (PSA) response to AA in relation to previous PSA response to ketoconazole was investigated. Methods: A retrospective analysis was conducted to determine the clinical activity of AA in men with CRPC who have received prior ketoconazole therapy at our institution. Time to PSA progression (PSA TTP) was defined by PCWG2 criteria, a PSA reduction of 50% or more was considered as PSA response. Results: Thirty four pts were identified. Nineteen pts (56%) had previous PSA responses on ketoconazole, with a median PSA TTP of 11 months (95% confidence interval [CI] 6.8-19.9). Subsequently, 11 of 34 (33%) of pts achieved a PSA response on AA, with a median PSA TTP of 6 months (95% CI 4.9-9.5). Among the 19 pts having a PSA response on ketoconazole, only four (21%) pts subsequently had PSA response to AA. Two of these pts had transient PSA response with PSA TTP less than 3 months on kKetoconazole, one patient discontinued Ketoconazole due to side effects, one patient had intermittent non-castrate testosterone levels. In contrast, 7 of 15 (46.7%) pts without prior PSA response to ketoconazole subsequently achieved PSA response on AA (p=0.11). Of note, PSA reduction of less than 50% on AA was observed in 9 of 34 pts (26%), which was associated with a longer median PSA TTP compared to pts who had PSA-progressive disease (5.9 months [95% CI 3.5-7.3] vs.1.5 months [95% CI 1.0-3.5], p=0.028). Five of these nine patients had a prior PSA response to ketoconazole but required drug discontinuation for reasons other than disease progression. Conclusions: PSA response to prior ketoconazole therapy is associated with lower PSA response rate to subsequent AA. The observation suggests that there is a biologically distinct subset of patients who are ketoconazole-resistant but abiraterone-sensitive, the underlying mechanism needs to be further investigated.


2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 308-308
Author(s):  
Onal Cem ◽  
Ali Murat Sedef ◽  
Fatih KOse ◽  
Ezgi Oymak ◽  
Ozan Cem Guler ◽  
...  

308 Background: The aim of this study is to evaluate the prognostic implications of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) at baseline and after 4 and 12 weeks of treatment with abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: We retrospectively evaluated 102 mCRPC treated with abiraterone either pre- or post-chemotherapy between November 2012 and October 2017 in three institutions. We calculated NLR and PLR at baseline and at 4 and 12 weeks after initiation of abiraterone, and we evaluated prostate-specific antigen (PSA) response every 4 weeks. Fifty patients (49%) were treated with abiraterone post-docetaxel, and 52 patients (51%) received abiraterone pre-chemotherapy. Based on receiver operating characteristic analysis, patients were stratified as low NLR ( < 3.1) or high NLR (≥ 3.1), and low PLR ( < 163) or high PLR (≥ 163). The cutoff for anemia was < 12g/dL. Results: Median follow-up times for patients overall and for those who survived were 24.0 months (range, 0.3 – 54.9 months) and 25.5 months (range, 2.8 – 54.9 months), respectively. The median time of abiraterone treatment was 8.1 months (range, 2.4 – 40.1 months). The median overall survival (OS) was 20.8 months (interquartile range: 17.3–24.4). In univariate analysis, NLR, PLR, PSA response, and low hemoglobin (Hgb) were found significantly predictive of OS and progression-free survival (PFS). In multivariate analysis, declines in NLR and PSA of ≥ 90% emerged as significant independent predictors of OS and PFS. High-NLR patients who remained high or who returned to low NLR after 4 and 12 weeks showed significantly worse OS than patients with low baseline NLR. Patients with baseline Hgb > 12 g/dL had significantly longer median OS compared with patients with Hgb ≤ 12 g/dL; however, the significance of Hgb was lost at 12 weeks. Conclusions: NLR and PSA response to abiraterone was a significant predictor of OS and PFS in mCRPC patients treated with abiraterone delivered either pre- or post-chemotherapy. Furthermore, persistent increase in NLR during abiraterone has prognostic value for OS in patients with mCRPC.


2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 358-358
Author(s):  
Delphine Borchiellini ◽  
Hakim Mahammedi ◽  
Julien Viotti ◽  
Gwenaelle Gravis ◽  
Guilhem Roubaud ◽  
...  

358 Background: Abiraterone acetate (AA), a CYP17A1 inhibitor, has been approved in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Germline polymorphisms in genes involved in androgen biosynthesis or transport may influence response and survival in this setting. Methods: ABIGENE is a multicentric prospective non-randomized pharmacogenetic study (NCT01858441). The primary objective was to investigate the association between 13 SNPs in genes related to AA pharmacology (CYP17A1, SLCO2B1 and SLCO2B3) and radiographic progression-free survival (rPFS), according to PCWG2 criteria, in pts with mCRPC treated with first-line AA + prednisone. The main secondary objectives were to evaluate the impact of these SNPs on radiographic and PSA response, overall survival (OS) and toxicity. SNPs were detected in blood samples before starting AA and analyzed by pyrosequencing or PCR-RFLP methods. Kaplan-Meyer’s curves with log-rank tests and cox regression models were used to identify relationships between SNPs and survival. Chi2 tests and student t-tests were used to identify association with response rate and toxicity. Results: 147 pts in 17 french centers were included between 2013 and 2017. Here are presented the results for the first 109 pts. The median follow-up was 28.7 months. Overall response rate (ORR) was 17%, and 74% pts had stable disease as the best response. Median rPFS was 10.9 months (95% CI 9.2-15.3). One SNP (rs10883782) in CYP17A1 was associated with rPFS on AA therapy (Table). Two other SNPs in CYP17A1 (rs4919683) and SLCO2B1 (rs1077858) were significantly associated with radiographic response. Data on PSA response, OS and toxicity will be presented at the meeting. Conclusions: This is the first prospective dedicated study to show an association between SNPs related to androgen metabolism and clinical outcome in mCRPC treated with AA. Clinical trial information: NCT01858441. [Table: see text]


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16507-e16507
Author(s):  
Katrin Schlack ◽  
Martin Boegemann ◽  
Laura-Maria Krabbe ◽  
Karoline Kannen ◽  
Axel Semjonow ◽  
...  

e16507 Background: Enzalutamide (Enza) prolongs survival in men with mCRPC in pre- and post chemotherapy setting. Commonly used prostate-specific antigen (PSA) may lead to non-straightforward prognosis. This is especially true for bone mCRPC (bmCRPC) in which initial bone-flare may add to difficult decision making. During other therapies, bouncing of alkaline phosphatase (ALP-Bounce) was shown as a promising surrogate for survival outcome. The purpose of this study was to evaluate the prognostic ability of ALP-Bounce compared to standard PSA and lactate dehydrogenase (LDH) after initiation of Enza. Methods: Patients with bmCRPC were included and analyzed. PSA, LDH and ALP were monitored at 2, 4, 8 and 12 weeks under very early Enza treatment. ALP-Bounce vs. no Bounce was analyzed using Kaplan-Meier estimates and uni- and multivariate (UV/MV) cox-regression models. ALP-Bounce was defined as an increase of ALP after initiation of Enza with a subsequent, significant decline below baseline during the first 8 weeks of therapy. Results: Eighty-nine men were evaluable for analysis. The median overall survival (OS) of men with ALP-Bounce was 19 months (95% confidence interval: 7.9-30.1) compared to 12 months (7.7-16.3) for no Bounce. Analysis of progression-free survival (PFS) showed similar results with 8 (0-16.3) vs. 3 months (1.9-4.1). In UV no ALP-Bounce (Hazard Ratio (HR): 1.9 (1.1-3.3); p = 0.02), no PSA-decline ≥50% (HR: 2.3 (1.5-3.7); p < 0.01) and no LDH-Normalization (HR: 2.5 (1.6-4.1); p < 0.01) were significantly associated with worse PFS. In MV only no ALP-Bounce showed a trend towards worse PFS (HR: 2.1 (0.9-4.5); p = 0.09). In UV no LDH-normalization was a significant prognosticator of poor OS (HR: 2.6 (1.6-4.2); p < 0.01) while ALP-Bounce and PSA decline ≥50% were non-prognostic. In MV no LDH-normalization remained an independent prognosticator of poor OS (HR: 2.0 (1.1.-3.5); p = 0.02). Conclusions: ALP-Bounce and LDH-Normalization may add to identification of bmCRPC-patients with favorable prognosis during early therapy with Enza. The early occurence of ALP-Bounce might be beneficial. These results have to be validated in a prospective trial.


2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 215-215 ◽  
Author(s):  
Pasquale Rescigno ◽  
David Lorente ◽  
Roberta Ferraldeschi ◽  
Diletta Bianchini ◽  
Spyridon Sideris ◽  
...  

215 Background: Falls in prostate specific antigen (PSA) levels by 50% from the baseline at 12 weeks are currently used to assess response to treatment for mCRPC (Scher et al, 2008). However PSA decline algorithms do not provide robust intermediate endpoints of overall survival (OS) benefit in mCRPC. We evaluated the association between PSA decline at 4 weeks and OS. Methods: We identified mCRPC patients who had received treatment with abiraterone acetate (AA) plus prednisolone post-docetaxel at the Royal Marsden (London, UK) between 01.01.2006 and 30.04.14. Patients were eligible for this analysis if they had PSA levels assessed at baseline, after 4 weeks and 12 weeks of treatment. PSA response at 4 weeks was defined as a ≥30% (PSA4w30) and ≥50% (PSA4w50) decline from baseline (PSABL). Association with outcome was analyzed using multivariate Cox regression and log-rank analyses. A significant p-value of 0.0167 was pre-specified to account for multiple testing. Demographics and clinical data were retrospectively collected from the hospital electronic patient record system (EPR). Results: We identified 124 patients who had received AA post-docetaxel and were eligible for this analysis. PSA4w30 was associated with longer OS (median OS 11.1 vs. 6.8 months; HR 0.50; 95% CI 0.32-0.80; p=.004). PSA4w50 was not associated with OS. A ≥50% PSA decline at 12 weeks (PSA12w50), the standard response measure, was also associated with OS (median OS 9.3 vs. 8.2; HR 0.49; 95% CI 0.29-0.80; p=.005). PSA4w30 was significantly associated with PSA12w50 (p<.001). Lack of a PSA response at 4 weeks correlated with a lack of response at 12 weeks (p=0.000), with a sensitivity of 84.9% [95% CI 75-91.4] and a specificity of 86.5% [95%CI 72–94.1]). PSA4w30 remained significantly correlated with OS (P<.001) in multivariate analyses including other established prognostic factors in mCRPC (ECOG PS, albumin, PSABL, ALP, LDH, Hemoglobin). Conclusions: Further studies to identify mCRPC patients not responding to treatment as early as possible are warranted; PSA4w30 may be useful to help identify patients unlikely to benefit from AA.


2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 261-261 ◽  
Author(s):  
Gerhardt Attard ◽  
Axel S. Merseburger ◽  
Cora N. Sternberg ◽  
Linda Cerbone ◽  
Federica Recine ◽  
...  

261 Background: AA is approved for mCRPC, coadministered with prednisone (P) (5 mg BID) to prevent adverse events (AEs) associated with mineralocorticoid excess (ME). Lower GC doses had not previously been formally evaluated in combination with AA. Methods: This was an open-label, multicenter, phase 2 trial (NCT01867710) of asymptomatic chemotherapy-naïve mCRPC pts randomized 1:1:1:1 to AA (1000 mg QD) plus P 5 mg BID or P 5 mg QD or P 2.5 mg BID or dexamethasone (DEX) 0.5 mg QD. Pts who had previously received GC or ketoconazole were excluded. The primary end point was no ME (% of pts experiencing neither hypokalemia nor hypertension during the first 24 weeks of treatment).Secondary end points included additional safety, as well as response rate in the first 24 weeks, defined as a decline in prostate-specific antigen (PSA) ≥ 50% confirmed after 4 weeks. Results: 164 pts were randomized; 133 (81.6%) completed 24 weeks’ treatment. Median age: 70 years. Table 1 shows the rates of ME, hypertension, hypokalemia and PSA response. Changes in HbA1c values were minimal and observed in 16 (10.7%) pts. Conclusions: These data suggest that P 5 mg BID, which is approved in combination with AA, and DEX 0.5 mg QD, are effective in preventing ME-associated AEs, and that P 2.5 mg BID and P 5 mg QD can be safely used with appropriate monitoring. The suggestion of a higher PSA response rate with DEX 0.5 mg QD arm warrants further validation. Clinical trial information: NCT01867710. [Table: see text]


2020 ◽  
Vol 6 (2) ◽  
pp. FSO436 ◽  
Author(s):  
Cecília M Alvim ◽  
André Mansinho ◽  
Rita S Paiva ◽  
Raquel Brás ◽  
Patrícia M Semedo ◽  
...  

Aim: To evaluate prostate-specific antigen response (PSAr) defined as a ≥50% decrease in PSA concentration from the pretreatment value, as a prognostic factor in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA). Methods: Retrospective evaluation of patients with mCRPC treated with AA. Results: 124 patients were identified. Median overall survival and progression-free survival for patients achieving PSAr versus patients without PSAr were 29.3 versus 9.7 months and 17.0 versus 5.2 months, respectively. Multivariate analysis confirmed that PSAr correlated with better overall survival (hazard ratio: 0.19; 95% CI: 0.10−0.38; p < 0.001) and progression-free survival (hazard ratio: 0.24; 95% CI: 0.14−0.41; p < 0.001). Conclusion: PSAr can be utilized as prognostic and predictive factors in mCRPC patients treated with AA.


2017 ◽  
Vol 12 (2) ◽  
pp. E47-52 ◽  
Author(s):  
Daniel Joseph Khalaf ◽  
Claudia M. Avilés ◽  
Arun A. Azad ◽  
Katherine Sunderland ◽  
Tilman Todenhöfer ◽  
...  

Introduction: Recently, a prognostic index including six risk factors (RFs) (unfavourable Eastern Cooperative Oncology Group performance status [ECOG PS], presence of liver metastases, short response to luteinizing hormone-releasing hormone [LHRH] agonists/ antagonists, low albumin, increased alkaline phosphatase [ALP] and lactate dehydrogenase [LDH]) was developed from the COUAA- 301 trial in post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate. Our primary objective was to evaluate this model in a cohort of chemotherapy-naive mCRPC patients receiving abiraterone.Methods: We identified 197 chemotherapy-naive patients who received abiraterone at six BC Cancer Agency centres and who had complete information on all six RFs. Study endpoints were prostate-specific antigen (PSA) response rate (RR), time to PSA progression, time on treatment, and overall survival (OS). PSA RR and survival outcomes were compared using Χ2 test and log-rank test. Multivariable Cox proportional hazard analysis was performed to identify RFs independently associated with OS.Results: Patients were classified into good (0‒1 RFs), intermediate (2‒3 RFs), and poor (4‒6 RFs) prognostic groups (33%, 52%, and 15%, respectively). For good-, intermediate-, and poor-risk patients, PSA RR (≥50% decline) was 60% vs. 42% vs. 40% (p=0.05); median time to PSA progression was 7.3 vs. 5.3 vs. 5.0 months (p=0.02); and median OS was 29.4 vs. 13.8 vs. 8.7 months (p<0.0001).Conclusions: The six-factor prognostic index model stratifies clinical outcomes in chemotherapy-naive mCRPC patients treated with abiraterone. Identifying patients at risk of poor outcome is important for informing clinical practice and clinical trial design.


2017 ◽  
Vol 11 ◽  
pp. 117955491773773 ◽  
Author(s):  
Masaomi Tatsuzawa ◽  
Ryuichi Ogawa ◽  
Naoki Kinjo ◽  
Soan Kim ◽  
Fumitaka Shimizu ◽  
...  

Background: Abiraterone acetate is an androgen synthesis inhibitor approved for the treatment of castration-resistant prostate cancer (CRPC). Although co-administration of either prednisone or prednisolone at 10 mg/d has been recommended to reduce the risk of abiraterone-induced hyperaldosteronism (notably hypokalemia) and to give adjunctive pain relief effects, whether these glucocorticoids can be substituted by dexamethasone remains unknown. Methods: We performed a retrospective review of medical records of patients who were given abiraterone for the treatment of CRPC with either prednisolone (ABI/PSL) 10 mg/d or dexamethasone (ABI/DEX) 0.5 or 1 mg/d between 2014 and 2017 in Juntendo University Nerima Hospital. Demographic and biochemical data including prostate-specific antigen (PSA) level were retrieved from the electronic medical records. Results: Fifty-three eligible patients (27 in ABI/PSL group and 26 in ABI/DEX group) were extracted from the records. Both groups showed no significant changes in serum potassium level before and after starting treatment. In the ABI/PSL group, 12 patients (46%) showed elevations of PSA and 7 patients (27%) discontinued treatment within 3 months. In contrast, in the ABI/DEX group, only 6 patients (25%) showed elevations of PSA and 3 patients (13%, all were given dexamethasone 1 mg/d) discontinued treatment. Conclusions: Dexamethasone and prednisolone may be equally effective in preventing abiraterone-induced hypokalemia.


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