To evaluate the safety and efficacy of abiraterone acetate (AA) in the “real life” clinical practice for men with chemotherapy-naïve metastatic castration-resistant prostate.
Cindolo et al BMC Cancer (2017) 17:753 DOI 10.1186/s12885-017-3755-x RESEARCH ARTICLE Open Access Safety and efficacy of abiraterone acetate in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: an Italian multicenter “real life” study Luca Cindolo1,14* , Clara Natoli2, Cosimo De Nunzio3, Michele De Tursi2, Maurizio Valeriani4, Silvana Giacinti5, Salvatore Micali6, Mino Rizzo6, Giampaolo Bianchi6, Eugenio Martorana6, Marcello Scarcia7, Giuseppe Mario Ludovico7, Pierluigi Bove8, Anastasia Laudisi9, Oscar Selvaggio10, Giuseppe Carrieri10, Maida Bada1, Pietro Castellan1, Stefano Boccasile11, Pasquale Ditonno11, Paolo Chiodini12, Paolo Verze13, Vincenzo Mirone13 and Luigi Schips1 Abstract Background: To evaluate the safety and efficacy of abiraterone acetate (AA) in the “real life” clinical practice for men with chemotherapy-naïve metastatic castration-resistant prostate Methods: A consecutive series of patients with mCRPC in Italian tertiary centres treated with AA was collected Demographics, clinical parameters, treatment outcomes and toxicity were recorded The Brief Pain Inventory scale Q3 was tracked and patient treatment satisfaction was evaluated Survival curves were estimated by the method of Kaplan-Meier and Cox regression and compared by the log-rank test statistic Results: We included 145 patients (mean age 76.5y) All patients were on androgen deprivation therapy Patients had prior radiotherapy, radical prostatectomy, both treatments or exclusive androgen deprivation therapy in 17%, 33%, 9% and 40%, respectively 57% of the patients had a Gleason score higher more than at diagnosis 62% were asymptomatic patients The median serum total PSA at AA start was 17 ng/mL (range 0,4–2100) The median exposure to AA was 10 months (range 1–35) The proportion of patients achieving a PSA decline ≥50% at 12 weeks was 49% Distribution of patient satisfaction was 32% “greatly improved”, 38% “improved”, 24% “not changed”, 5.5% “worsened” Grade and toxicity was recorded in 17/145 patients 11.7% (70% cardiovascular events, 30% critical elevation of AST/ALT levels) At the last follow-up, median progression free and overall survival were 17 and 26 months, respectively Both outcomes significantly correlated with the presence of pain, patient satisfaction, PSA baseline and PSA decline Conclusions: The AA is effective and well tolerated in asymptomatic or slightly symptomatic mCRPC in a “real life” setting The survival outcomes are influenced by the presence of pain, patient satisfaction, baseline PSA and PSA decline (Continued on next page) * Correspondence: lucacindolo@virgilio.it Department of Urology, ASL Abruzzo2, Via dei Vestini, Chieti, Italy 14 Department of Urology, ASL Abruzzo2 , “S Pio da Pietrelcina” Hospital, Via San Camillo de Lellis 1, Vasto, Italy Full list of author information is available at the end of the article © The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated Cindolo et al BMC Cancer (2017) 17:753 Page of (Continued from previous page) Trial registration: The study was retrospectively registered at ISRCTN as DOI:10.1186/ISRCTN 52513758 in date April the 30th 2016 Keywords: Prostate cancer, Androgen deprivation therapy, Abiraterone acetate, Castration-resistant prostate cancer, Androgen receptor Background Prostate cancer (PCa) is the most common male neoplasm and the second leading cause of death from cancer [1] External beam radiation therapy and surgery are the best options for the treatment of a localized disease, however after an initial treatment with curative intent almost 34% of patients developed progressive metastatic disease [2] Currently, about 5% of the men were newly diagnosed with metastatic PCa, compared with 20–25% >20 yr ago [3] For patients with progressive, recurrent and/or metastatic PCa the androgen deprivation therapy (ADT) is the main therapeutic option, even though the progression to a castration-resistant state invariably occurs after a median time of 18–24 months [3] The median time from the diagnosis of metastatic disease to death is about 40 months The metastatic castration-resistant prostate cancer (mCRPC) is the final common pathway in the disease continuum of PCa and remains a clinically relevant phenotype with an elevated burden of mortality Several mechanisms have been proposed to explain the acquisition of the castration-resistant prostate cancer status including the upregulation of the androgen receptor (AR), induction of AR splice variants, AR point mutations, upregulation of glucocorticoid receptors, activation of alternative oncogenic signaling pathways, neuroendocrine transformation and immune evasion via PD-L1 upregulation [4, 5] Nowadays several treatments are available for the management of mCRPC prior to chemotherapy In particular, abiraterone acetate (AA) has been used in several studies and in different clinical settings, demonstrating the reliability and the robustness of the oncological results of AA in terms of overall survival, PSA progression, radiological free survival, time to opiate, etc [6–12] Notwithstanding these RCTs, few studies have evaluated the role of AA in managing chemonaive mCRPC in a “real life” setting [12, 13] The aim of our study was to evaluate the safety and efficacy of AA plus the prednisone regimen in mCRPC chemotherapy-naive patients in an Italian multicentre “real life” study Methods Patients and measures The study was registered at ISRCTN as DOI:10.1186/ ISRCTN 52513758 A consecutive series of 145 (November 2013–June 2016) patients with progressive mCRPC and castrate levels of testosterone (2 (5) Presence of Pain, yes, n (%) 56 (38.6) Brief Pain Inventory Question #3, >2, n (%), (missing =13) 46 (34.9) Baseline PSA, median (range) 17.4 (0.4 to 2100.0) Baseline ALT, median (range) 20 (8–87) Baseline AST, median (range) 18.5 (6–309) Gleason at time of initial diagnosis, n (%) (missing = 4) >7 81 (57.5) Local treatment, n (%) None 58 (40.0) External Beam Radiation Therapy 25 (17.2) Radical Prostatectomy 49 (33.8) Both 13 (8.9) Disease location, n (%) (missing =5) Foundation for Statistical Computing, Vienna, Austria) Continuous variables were reported as either mean and standard deviation (SD) or median and range on the basis of their distribution Comparisons of variables among groups were performed by the one-way ANOVA or Kruskal–Wallis test Categorical variables were expressed as the absolute number and percentage and analyzed by the Chi-square test Survival curves were estimated by the product-limit method of Kaplan-Meier and compared using the log-rank statistics The Cox regression model was used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) An alpha value of 5% was considered as the threshold for significance Results Overall, 145 patients who initiated AA between November 2013 and June 2016 were enrolled Table summarizes the characteristics of the patient cohort In particular, the median age was 76.5 years and 33.8% had already received surgery, whereas 40% of the patients were treated with ADT only Patients with a Gleason score higher than at diagnosis represented 57.5% of the series About 38% of patients were symptomatic prior to the initiation of AA, with an ECOG-PS ranging between and in 93% of subjects Only 11% of patients received more than hormonal manipulations before AA The ADT lasted more than 12 months in 77.9% of patients, with a median time of mCRPC development of years The median serum total PSA at baseline was 17.4 ng/mL (range 0.4–2100) Overall the median Table Treatment details Variable Value N of cycles of AA, median (range) 10 (1–35) Bone only 75 (53.5) Last PSA, median (range), n = 130 9.7 (0.0 to 2743.0) Lymph nodes only 22 (15.7) 12 weeks PSA, median (range), n = 99 7.7 (0.0 to 900.0) Visceral only (2.8) 12 weeks PSA decline, n (%), n = 99 49 (49.5) Prostatic fossa only 11 (7.8) 12 weeks ALT, median (range), n = 58 22 (88–215) Multiple sites 28 (20.0) 12 weeks AST, median (range), n = 58 23 (9–150) Comorbidity, n (%) Patients’ subjective impression on AA regimen, n = 108 (missing =27) None 33 (22.7) = greatly improved 35 (32.4) Cardiovascular only 50 (35.7) = improved 41 (37.9) Metabolic only (5.5) = not changed 26 (24.0) Multiple (cardiovascular + metabolic) 26 (17.9) = worsened (5.5) Other 28 (19.3) Median follow-up time, month (IQR) 13.6 (7–16) Time to mCRPC from initial diagnosis years, median (range) 5.0 (0.2 to 17.7) Death, n (%) 33 (22.8) Hormonal manipulations before AA >2, n (%) 22 (15.2) Progression, n (%) 56 (38.6) Median PFS, month (95% CI) 18.5 (16–20) Median OS, month (95% CI) 26.5 (21–32) Duration of ADT >12 m, n (%) 113 (77.9) Abreviations: mCRPC metastatic castration resistant prostate cancer, ECOG Eastern Cooperative Oncology Group, PSA prostate specific antigen, AA abiraterone acetate, ALT alanine aminotransferase, AST aspartate aminotransferase, ADT androgen deprivation therapy Abreviations: PSA prostate specific antigen, AA abiraterone acetate, ALT alanine aminotransferase, AST aspartate aminotransferase, PFS progression free survival, OS overall survival Cindolo et al BMC Cancer (2017) 17:753 Page of Fig Waterfall plot showing the 12w PSA decline in patients with follow-up >3 months (%) A negative percentage indicates a decline in PSA A positive percentage indicates that the patient never had a decline in PSA exposure to AA was 10mo (range 1–35) (1 cycle = month), with a 51% rate of dropout (66% for disease progression/clinical deterioration, 14.8% for death, 10.8% lost to follow-up, 8.1% for toxicity) (Table 2) Specifically, relevant toxicity (Grade and 4) was recorded in 17 out of 145 patients (11.7%): 12 had cardiovascular events, had a critical elevation of AST/ALT levels (within the 4th month) At the last follow up 50.3% of the patients were still on active treatment with a median PSA of 9,7 ng/mL Fig PFS according to different clinical variables: a) Pain (solid line = no; dotted line = yes); b) patient satisfaction in patients with follow-up >3 months (solid line = satisfied + very satisfied; dotted line = worsened + not modified); b) baseline PSA (solid line = 3 months (solid line = 3 months (solid line = satisfied + very satisfied; dotted line = worsened + not modified); c) baseline PSA (solid line = 3 months (solid line =