BACKGROUND:Androgen-deprivation therapy (ADT) plus radiotherapy is a standard of care for men with high-risk localized prostate cancer (PC). Adding docetaxel in this setting demonstrated better relapse-free survival (RFS) but not survival. Few data are available on relapse patterns. Our aim was to investigate whether different patterns of relapses exist in men with high-risk localized PC. PATIENTS AND METHODS:Prospective data from the GETUG12 phase 3 randomized controlled trial comparing ADT alone vs ADT + docetaxel and estramustine (DE) was examined. RFS (main endpoint) was analysed using parametric survival models and second event-free survival (SEFS) defined from biochemical progression (BP) was analysed using a competing-risk approach. RESULTS:Overall, 413 patients were randomized from 2002 to 2006, 206 treated with ADT and 207 with ADT+DE, in addition to local treatment. First analysis showed that the piecewise-exponential model with two time-intervals ([0-3[; ≥3 years) was the model that best characterized RFS with no time-dependent effect of risk factors and treatment. Second analyses limited to patients with a BP showed that the risk of a second event was significantly lower in patients with a longer time-interval from randomization to BP (hazard ratio (HR≥ 3 versus < 3 years): 0.49 [95% CI 0.30-0.79]). In competing-risk analysis, a significant and protective effect of this time-interval was observed for metastases (sub-HR≥ 3 versus < 3 years: 0.41 [0.23-0.73] accounting for salvage treatment. CONCLUSION:Time-interval from randomization to BP is a major prognostic factor for developing local or distant recurrences for patients with high-risk localized PC.

Background and objective Docetaxel has become a standard component of care for advanced prostate cancer (PC); however, its benefits are not universal among patients. A subset of PC cases exhibit TMPRSS2-ERG gene fusion, resulting in ERG overexpression in tumors. Our aim was to assess biomarkers for docetaxel efficacy in men with hormone-sensitive PC (HSPC). Methods Pretreatment prostate biopsies were obtained from participants in two randomized phase 3 clinical trials investigating docetaxel in high-risk localized PC (GETUG 12) and metastatic HSPC (GETUG 15). Immunohistochemistry staining for Ki67, PTEN, RB, and phosphorylated RB was conducted for GETUG 12 samples, and ERG staining for GETUG 12 and GETUG 15 samples. We examined biomarker association with outcomes using univariate and multivariable analyses adjusted for other validated prognostic factors. Key findings and limitations Among GETUG 12 patients, Ki67 was associated with a worse relapse-free survival (RFS; hazard ratio [HR] 1.72; p = 0.0092). A pooled analysis for the two trials (pinteraction = 0.056) revealed that docetaxel-based chemotherapy improved failure-free survival for patients with ERG-positive cancer (HR 0.58; p = 0.03), but not patients with ERG-negative cancer (HR 1.08; p = 0.72). In the ERG-positive subgroup in GETUG 12 (high-risk localized PC), median RFS was 7.79 yr with androgen deprivation therapy (ADT) alone, and was not reached with ADT + docetaxel. In the ERG-negative subgroup, median progression-free survival (mPFS) was 7.79 yr with ADT alone versus 7.08 yr with ADT + docetaxel. In the ERG-positive subgroup in GETUG 15 (metastatic HSPC), mPFS was 10.7 mo with ADT alone versus 18.8 mo with ADT + docetaxel. In the ERG-negative subgroup, mPFS was 10.6 mo with ADT alone versus 13.2 mo with ADT + docetaxel. Conclusions and clinical implications Ki67 may serve as a prognostic factor in HSPC, while ERG expression appears to predict a response to docetaxel in both high-risk localized and metastatic HSPC. Patient summary We assessed factors that could predict outcomes after docetaxel chemotherapy in patients with advanced prostate cancer. We found that expression of a protein called ERG can predict a good response to docetaxel in these patients.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.GETUG-13 established that switching patients with poor-prognosis nonseminomatous germ-cell tumors with an unfavorable marker decline to intensified chemotherapy resulted in improved outcomes. Here, we report the GETUG-13 long-term efficacy and toxicity. Two hundred and sixty-three patients with International Germ Cell Cancer Consensus Group poor prognosis received one cycle of bleomycin, etoposide, and cisplatin (BEP): 51 with a favorable tumor marker decline continued with three cycles of BEP (Fav-BEP) and 203 with an unfavorable decline were randomly treated with three BEP (Unfav-BEP) cycles or a dose-dense regimen (Unfav-dose-dense; two cycles of paclitaxel-BEP-oxaliplatin + two cycles of cisplatin, ifosfamide, and bleomycin). The median follow-up was 7.1 years (range, 0.3-13.3). Five-year progression-free survival (PFS) rates were 58.9% in the Unfav-dose-dense arm and 46.7% in the Unfav-BEP arm (hazard ratio [HR], 0.65 [95% CI, 0.44 to 0.97]; P = .036). Five-year overall survival rates were 70.9% and 61.3% (HR, 0.74 [95% CI, 0.46 to 1.20]; P = .22). Side effects evolved favorably, with only three patients in the Unfav-dose-dense arm reporting grade 3 motor neurotoxicity at 1 year and no reported toxicity over grade 1 after year 2. Salvage high-dose chemotherapy plus a stem-cell transplant was used in 8% in the Unfav-dose-dense arm and 17% in the Unfav-BEP arm (P = .035). Long-term outcomes suggest a sustained benefit of intensified chemotherapy in terms of PFS and numerically better survival, with a minimal toxicity and reduced use of salvage high-dose chemotherapy plus stem-cell transplant.

INTRODUCTION:Serum prostate specific antigen (PSA) is a well-known prognostic parameter in men with prostate cancer. The treatment of men with very high PSA values and apparently no detectable metastases is not fully established. PATIENTS AND METHODS:Ancillary analysis from the GETUG 12 phase 3 trial. Patients with non-metastatic high-risk prostate cancer by bone and computerized tomography (CT) scan were randomly assigned to receive androgen deprivation therapy (ADT) and docetaxel plus estramustine or ADT alone. Relapse-free survival (RFS), clinical RFS, metastases-free survival (MFS), overall survival (OS), and prostate cancer-specific survival (PCSS) were estimated using the Kaplan-Meier method for different levels of PSA (50 ng/mL, 75 ng/mL, and 100 ng/mL). The relationship between PSA and outcomes was studied using residual-based approaches and spline functions. RESULTS:The median follow-up was 12 years (range: 0-15.3). Baseline PSA (<50 ng/mL, n = 328; ≥50ng/mL, n = 85) was associated with improved RFS (P = .0005), cRFS (P = .0024), and MFS (P = .0068). The 12-year RFS rate was 46.33% (CI 40.59-51.86), 33.59% (CI 22.55-44.97), and 11.76% (1.96-31.20) in men with PSA values <50 ng/mL (n = 328), 50-100 ng/mL (n = 68), and ≥100 ng/mL (n = 17), respectively. Exploratory analyses revealed no deviation from the linear relationship assumption between PSA and the log hazard of events. CONCLUSIONS:Men with apparently localized prostate cancer and a high baseline PSA value have a reasonable chance of being long-term disease-free when treated with curative intent combining systemic and local therapy.

In 2014, the GETUG 13 trial has established the role of early intensified treatment for men with poor prognosis germ-cell tumors (GCT) and unfavorable tumor marker decline (Fizazi K, Lancet Oncol 2014). Patients with unfavorable marker decline were randomized after 1 cycle of BEP to receive either 3 additional BEP or dose-dense chemotherapy with personalized cumulative doses of bleomycin (potentially exceeding the 300 mg recommended threshold) based on serial lung function assessments. We assessed pulmonary toxicity of this strategy.

BACKGROUND:There is growing evidence that a high neutrophil-to-lymphocyte ratio (NLR) is associated with poor overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC). In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and OS versus abiraterone or enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative androgen-receptor-targeted agent (ARTA). Here, we investigated NLR as a biomarker. PATIENTS AND METHODS:CARD was a multicenter, open-label study that randomized patients with mCRPC to receive cabazitaxel (25 mg/m2 every 3 weeks) versus abiraterone (1000 mg/day) or enzalutamide (160 mg/day). The relationships between baseline NLR [< versus ≥ median (3.38)] and rPFS, OS, time to prostate-specific antigen progression, and prostate-specific antigen response to cabazitaxel versus ARTA were evaluated using Kaplan-Meier estimates. Multivariable Cox regression with stepwise selection of covariates was used to investigate the prognostic association between baseline NLR and OS. RESULTS:The rPFS benefit with cabazitaxel versus ARTA was particularly marked in patients with high NLR {8.5 versus 2.8 months, respectively; hazard ratio (HR) 0.43 [95% confidence interval (CI) 0.27-0.67]; P < 0.0001}, compared with low NLR [7.5 versus 5.1 months, respectively; HR 0.69 (95% CI 0.45-1.06); P = 0.0860]. Higher NLR (continuous covariate, per 1 unit increase) independently associated with poor OS [HR 1.05 (95% CI 1.02-1.08); P = 0.0003]. For cabazitaxel, there was no OS difference between patients with high versus low NLR (15.3 versus 12.9 months, respectively; P = 0.7465). Patients receiving an ARTA with high NLR, however, had a worse OS versus those with low NLR (9.5 versus 13.3 months, respectively; P = 0.0608). CONCLUSIONS:High baseline NLR predicts poor outcomes with an ARTA in patients with mCRPC previously treated with docetaxel and the alternative ARTA. Conversely, the activity of cabazitaxel is retained irrespective of NLR.

16 Background: The CARD NCT02485691 study reported superior rPFS and OS with CBZ vs abiraterone or enzalutamide in patients with mCRPC who progressed on docetaxel and within 12 months on a previous alternative androgen-signaling-targeted inhibitor (ARTA). This analysis evaluated changes in pain and HRQL associated with CBZ and ARTA during the CARD study. Methods: Pain response was defined as a decrease > 30% from baseline in BPI-SF pain intensity score with no increased analgesic use. HRQL was assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Patients were evaluable if they had received at least one dose of CBZ or ARTA and had a baseline FACT-P score plus at least one subsequent FACT-P measurement. A clinically meaningful improvement or deterioration of total FACT-P score was defined as a difference of ± 10 points from baseline. Clinically meaningful changes in HRQL and pain response were confirmed at two consecutive evaluations ≥ 3 weeks apart during the on-treatment period. Survival curves were generated by Kaplan–Meier estimates. Results: Of the 255 patients randomized, 172 (67.5%) had moderate to severe pain at randomization. Pain response and HRQL were evaluable for 111 (86.0%) and 108 (83.7%) for CBZ and 109 (86.5%) and 114 (90.5%) for ARTA. Pain response was 45.9% vs 19.3% for CBZ vs ARTA (p < 0.0001). The probability of not having pain progression after 12 months was 66.2% vs 45.3% CBZ vs ARTA (HR 0.55; 95% CI 0.32–0.97; p = 0.0348). An improvement in total FACT-P score from baseline was reported by 27 (25.0%) patients vs 26 (22.8%) for CBZ vs ARTA. FACT-P score was maintained or improved for 81 (75.0%) patients with CBZ and 86 (75.4%) patients with ARTA. A deterioration in FACT-P from baseline was reported by 22.2% with CBZ vs 24.6% with ARTA. Median time to FACT-P deterioration was 14.8 months for CBZ vs 8.9 months for ARTA (HR 0.72; 95% CI 0.44–1.20; p = 0.2072). Conclusions: CBZ was associated with a greater pain response and delayed pain progression vs ARTA. CBZ and ARTA were associated with similar trends in HRQL but time to FACT-P deterioration was longer with CBZ vs ARTA. Clinical trial information: NCT02485691.

5569 Background: The CARD trial (NCT02485691) compared cabazitaxel vs. an androgen receptor targeted agent (ART; abiraterone/enzalutamide) in mCRPC previously treated with docetaxel and the alternative ART (abiraterone/enzalutamide), in any order. These post hoc analyses assessed OS from various time points and the impact of prognostic factors. Methods: Patients with mCRPC previously treated with docetaxel and progressing ≤ 12 months on prior abiraterone/enzalutamide were randomized 1:1 to cabazitaxel (25 mg/m2 IV Q3W + daily prednisone + prophylactic G-CSF) vs. abiraterone (1000 mg PO + daily prednisone) or enzalutamide (160 mg PO). OS was calculated from date of diagnosis of metastatic disease, date of mCRPC, and start of 1st, 2nd or 3rd life-extending therapy (LET). A stratified multivariate Cox regression analysis assessed the impact of 14 prognostic factors on OS using a stepwise model selection approach with a significance level of 0.10 for entry into the model and 0.05 for removal. Results: In the CARD study (N = 255), median OS was longer with cabazitaxel vs. abiraterone/enzalutamide (13.6 vs 11.0 months; HR 0.64, 95% CI 0.46–0.89; p = 0.008). OS was numerically improved for cabazitaxel vs. abiraterone/enzalutamide when assessed from the time of diagnosis of metastatic disease or mCRPC, or from start of 1st or 2nd LET (Table). In the multivariate analysis, low hemoglobin, high baseline neutrophil to lymphocyte ratio, and high PSA values at baseline were associated with worse OS. In presence of these factors, the OS benefit observed with cabazitaxel versus abiraterone/enzalutamide remained significant (HR 0.63, 95% CI 0.42–0.94, p = 0.022). Conclusions: Cabazitaxel numerically improved OS vs. abiraterone/enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative ART (abiraterone/enzalutamide), whatever the time point considered. The robustness of this OS benefit was confirmed by stratified multivariate analysis. Sanofi funded. Clinical trial information: NCT02485691 . [Table: see text]

Background: Induction chemotherapy is recommended before surgery for unresectable muscle-invasive bladder cancer, locally advanced or lymph node disseminated disease. These patients’ prognoses cannot be extrapolated from data regarding neoadjuvant chemotherapy, which is performed in operable patients. Objective: We assessed the prognosis of patients undergoing induction chemotherapy for locally advanced or lymph node metastatic bladder cancer. Methods: We analysed patients with cT4NxM0 or cTxN+M0 bladder cancer treated by induction chemotherapy between 2006 and 2016. The tumour extension and node invasion was determined by imaging or histologically after upfront lymph node dissection. Clinical, biological, pathological and patient follow-up data were identified. Kaplan–Meier survival curves were compared by log rank test. Factors associated with the response to induction chemotherapy, operability of patients and survival were determined by multivariable logistic regression. Results: Among 70 patients included in the analysis, 51 (73%) showed response to induction chemotherapy. Progression-free and overall survival were improved in responder patients compared with non-responders ( P<0.0001 and P=0.025, respectively) and for patients who underwent surgery compared with non-operated patients (both P<0.001). On multivariable analysis, poor response was associated with chemotherapy other than methotrexate, vinblastine, doxorubicin and cisplatin ( P=0.016), operability with late response ( P=0.0024) and overall survival with surgery after induction chemotherapy ( P=0.0014). Conclusions: Surgery after induction chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin may improve prognosis with locally advanced or lymph node metastatic bladder cancer. Level of evidence: 4

High NLR as a biomarker of inflammation is associated with poor overall survival (OS) in different malignancies, including mCRPC (Lorente et al, Ann Oncol 2015). The CARD study (NCT02485691) reported improved radiographic progression-free survival (rPFS) and OS with CBZ vs abiraterone or enzalutamide in patients with mCRPC who previously received docetaxel and progressed within 12 months on the alternative androgen receptor-targeted agent (ARTA) (de Wit et al, N Engl J Med 2019). This analysis of CARD evaluated the impact of baseline NLR on outcomes. Multivariable Cox regression analysis with stepwise selection of covariates (stratification factors and pre-planned prognostic factors), including adjustment for treatment, was used to investigate the prognostic association between baseline NLR (as a continuous variable) and OS. The associations between baseline NLR (< vs ≥ median), and OS, rPFS, time to prostate-specific antigen (PSA) progression, and PSA response (confirmed PSA decline ≥ 50% from baseline) were also evaluated. Baseline median NLR in both arms overall was 3.38; higher baseline NLR independently associated with poor OS (HR [95% CI]: 1.05 [1.02–1.08]; p = 0.0003). Additional factors associated with poor OS were lower hemoglobin and high PSA at baseline. Greater clinical activity in terms of rPFS, time to PSA progression and PSA response was seen with CBZ irrespective of baseline NLR, with the benefits of CBZ vs ARTA particularly marked in patients with NLR ≥ median (Table). CBZ also significantly prolonged OS vs ARTA in patients with baseline NLR ≥ median (HR [95% CI]: 0.49 [0.30–0.81]; log-rank p = 0.004).Table: 629PNLR ≥ medianNLR < medianCBZ (n = 63)ARTA (n = 60)CBZ (n = 62)ARTA (n = 61)Median rPFS, months (95% CI)8.5 (4.9–11.4)2.8 (2.7–4.5)7.5 (5.4–8.5)5.1 (3.1–7.0)Median OS, months (95% CI)*15.3 (11.8–20.3)9.5 (9.0–11.8)12.9 (10.5–19.1)13.3 (9.3–17.3)CBZ (n = 56)ARTA (n = 52)CBZ (n = 56)ARTA (n = 50)Time to PSA progression, months (95% CI)*6.9 (3.5–10.3)2.1 (1.7–2.8)5.8 (3.5–8.8)2.1 (1.4–2.8)PSA response, %*37.517.335.712.0* Post-hoc analyses. Open table in a new tab * Post-hoc analyses. This present analysis of CARD confirms that NLR is prognostic for poor outcomes in mCRPC. The superiority of CBZ vs a second ARTA was particularly marked in patients with high baseline NLR.

5559 Background: In the CARD (NCT02485691) study, radiographic PFS (rPFS), PFS and OS were significantly improved with CBZ vs. androgen-signaling-targeted agents (ARTA; ABI or ENZ) in pts with mCRPC who had received docetaxel (DOC) and progressed within 12 months (mo) on an alternative ARTA. This analysis evaluated the impact of age (< 70 vs. ≥ 70 years) on the efficacy and safety of CBZ and ARTAs in CARD. Methods: 255 pts with mCRPC were randomized 1:1 to CBZ (25 mg/m2 IV Q3W + prednisone [P] + G-CSF) vs. ABI (1000 mg PO + P) or ENZ (160 mg PO) until disease progression, unacceptable toxicity or pt request. Pts were eligible if they had received ≥ 3 cycles of DOC and progressed ≤ 12 mo on the previous alternative ARTA. Primary endpoint was rPFS. Subgroup analysis of older (≥ 70 years; n = 135) and younger (< 70 years; n = 120) pts was pre-specified for rPFS; others were post hoc. Results: rPFS was significantly improved vs. ARTA in both older (median 8.2 vs. 4.5 mo; HR 0.58; 95% CI 0.38–0.89) and younger pts (median 7.4 vs. 3.2 mo; HR 0.47; 95% CI 0.30–0.74). Median OS for CBZ vs. ARTA was 13.9 vs. 9.4 mo (HR 0.66; 95% CI 0.41–1.06) in older pts and 13.6 vs. 11.8 mo (HR 0.66; 95% CI 0.41–1.08) in younger pts. PFS, tumor, PSA and pain responses also favored CBZ, regardless of age. Grade ≥ 3 adverse events (AEs) occurred in 57.8% vs. 49.3% of older pts receiving CBZ vs. ARTA and 48.4% vs. 42.1% in younger pts. AEs leading to death were more frequent with ARTA, mainly due to disease progression. Conclusions: CBZ had improved efficacy outcomes vs. ARTA in pts with mCRPC previously treated with DOC and the alternative ARTA, regardless of age. Grade ≥ 3 cardiac AEs were more frequent in older pts treated with ARTA. A higher rate of AEs was reported in older vs. younger pts, for ARTA and CBZ. CBZ and ARTA had different safety profiles in older compared with younger pts. Clinical trial information: NCT02485691 . Funding: Sanofi. [Table: see text]

BACKGROUND:In the CARD study, cabazitaxel significantly improved radiographic progression-free survival and overall survival versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and the alternative androgen signalling-targeted inhibitor. Here, we report the quality-of-life outcomes from the CARD study. METHODS:CARD was a randomised, multicentre, open-label, phase 4 study involving 62 clinical sites across 13 European countries. Patients (aged ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status ≤2) with confirmed metastatic castration-resistant prostate cancer were randomly assigned (1:1) by means of an interactive voice-web response system to receive cabazitaxel (25 mg/m2 intravenously every 3 weeks, 10 mg daily prednisone, and granulocyte colony-stimulating factor) versus abiraterone (1000 mg orally once daily plus 5 mg prednisone twice daily) or enzalutamide (160 mg orally daily). Stratification factors were ECOG performance status, time to disease progression on the previous androgen signalling-targeted inhibitor, and timing of the previous androgen signalling-targeted inhibitor. The primary endpoint was radiographic progression-free survival; here, we present more detailed analyses of pain (assessed using item 3 on the Brief Pain Inventory-Short Form [BPI-SF]) and symptomatic skeletal events, alongside preplanned patient-reported outcomes, assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and the EuroQoL-5 dimensions, 5 level scale (EQ-5D-5L). Efficacy analyses were done in the intention-to-treat population. Pain response was analysed in the intention-to-treat population with baseline and at least one post-baseline assessment of BPI-SF item 3, and patient-reported outcomes (PROs) were analysed in the intention-to-treat population with baseline and at least one post-baseline assessment of either FACT-P or EQ-5D-5L (PRO population). Analyses of skeletal-related events were also done in the intention-to-treat population. The CARD study is registered with ClinicalTrials.gov, NCT02485691, and is no longer enrolling. FINDINGS:Between Nov 17, 2015, and Nov 28, 2018, of 303 patients screened, 255 were randomly assigned to cabazitaxel (n=129) or abiraterone or enzalutamide (n=126). Median follow-up was 9·2 months (IQR 5·6-13·1). Pain response was observed in 51 (46%) of 111 patients with cabazitaxel and 21 (19%) of 109 patients with abiraterone or enzalutamide (p<0·0001). Median time to pain progression was not estimable (NE; 95% CI NE-NE) with cabazitaxel and 8·5 months (4·9-NE) with abiraterone or enzalutamide (hazard ratio [HR] 0·55, 95% CI 0·32-0·97; log-rank p=0·035). Median time to symptomatic skeletal events was NE (95% CI 20·0-NE) with cabazitaxel and 16·7 months (10·8-NE) with abiraterone or enzalutamide (HR 0·59, 95% CI 0·35-1·01; log-rank p=0·050). Median time to FACT-P total score deterioration was 14·8 months (95% CI 6·3-NE) with cabazitaxel and 8·9 months (6·3-NE) with abiraterone or enzalutamide (HR 0·72, 95% CI 0·44-1·20; log-rank p=0·21). There was a significant treatment effect seen in changes from baseline in EQ-5D-5L utility index score in favour of cabazitaxel over abiraterone or enzalutamide (p=0·030) but no difference between treatment groups for change from baseline in EQ-5D-5L visual analogue scale (p=0·060). INTERPRETATION:Since cabazitaxel improved pain response, time to pain progression, time to symptomatic skeletal events, and EQ-5D-5L utility index, clinicians and patients with metastatic castration-resistant prostate cancer can be reassured that cabazitaxel will not reduce quality of life when compared with treatment with a second androgen signalling-targeted inhibitor. FUNDING:Sanofi.

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) II (PD16)1 Apr 2020PD16-08 EFFECT OF CABAZITAXEL VS ABIRATERONE OR ENZALUTAMIDE ON PATIENT-REPORTED OUTCOMES IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER: A PRE-PLANNED EQ-5D-5L ANALYSIS OF THE CARD STUDY Gero Kramer*, Cora N. Sternberg, Karim Fizazi, Bertrand Tombal, Jean-Christophe Eymard, Johann De Bono, Daniel Castellano, Christian Wülfing, Michail Liontos, Joan Carles, Roberto Iacovelli, Bohuslav Melichar, Ásgerður Sverrisdóttir, Christine Theodore, Susan Feyerabend, Carole Helissey, Ayse Ozatilgan, Christine Geffriaud-Ricouard, and Ronald de Wit Gero Kramer*Gero Kramer* More articles by this author , Cora N. SternbergCora N. Sternberg More articles by this author , Karim FizaziKarim Fizazi More articles by this author , Bertrand TombalBertrand Tombal More articles by this author , Jean-Christophe EymardJean-Christophe Eymard More articles by this author , Johann De BonoJohann De Bono More articles by this author , Daniel CastellanoDaniel Castellano More articles by this author , Christian WülfingChristian Wülfing More articles by this author , Michail LiontosMichail Liontos More articles by this author , Joan CarlesJoan Carles More articles by this author , Roberto IacovelliRoberto Iacovelli More articles by this author , Bohuslav MelicharBohuslav Melichar More articles by this author , Ásgerður SverrisdóttirÁsgerður Sverrisdóttir More articles by this author , Christine TheodoreChristine Theodore More articles by this author , Susan FeyerabendSusan Feyerabend More articles by this author , Carole HelisseyCarole Helissey More articles by this author , Ayse OzatilganAyse Ozatilgan More articles by this author , Christine Geffriaud-RicouardChristine Geffriaud-Ricouard More articles by this author , and Ronald de WitRonald de Wit More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000859.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The results of the CARD (NCT02485691) study demonstrated superiority of cabazitaxel (CBZ) vs abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on docetaxel and within 12 months on a prior alternative androgen-signaling-targeted inhibitor (ARTA). This pre-planned analysis evaluated changes in EQ-5D-5L score following treatment with CBZ or ARTA. METHODS: Patient-reported outcomes (PROs) were evaluated using the EQ-5D-5L utility index and visual analogue scale (VAS). Scores were evaluated at baseline, on Day 1 of each cycle and at the end of treatment (EOT) visit. Patients were evaluable if they had received at least one dose of CBZ or ARTA and had an EQ-5D-5L assessment at baseline and at least one subsequent assessment. A mixed-effect model repeated measures analysis of EQ-5D-5L changes from baseline was performed. RESULTS: Of the 255 patients randomized, 230 were evaluable for EQ-5D-5L, with 115 (89.1%) for CBZ and 115 (91.3%) for ARTA. At baseline, both groups had comparable mean values for utility index (0.70 for both) and VAS (65.8 vs 66.3 for CBZ vs ARTA, respectively). Changes in VAS and utility index scores from baseline during treatment and EOT favored CBZ vs ARTA. The least squares mean difference for CBZ vs ARTA ranged 1.6 to 6.4 (5.9 at EOT) for VAS and from 0.03 to 0.08 and (0.05 at EOT) for utility index. At baseline, moderate-to-severe or extreme pain/discomfort, evaluated by EQ-5D-5L, was reported by 45 (39.1%) for CBZ and 47 (40.9%) for ARTA, respectively. CBZ was associated with a greater proportion of patients reporting pain/discomfort improvement from baseline (figure). Similar trends were seen across all EQ-5D-5L subscales. CONCLUSIONS: CBZ showed a greater improvement in PROs measured by EQ-5D-5L vs abiraterone or enzalutamide in patients previously treated with docetaxel and the alternative ARTA. Source of Funding: Sanofi © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e366-e366 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Gero Kramer* More articles by this author Cora N. Sternberg More articles by this author Karim Fizazi More articles by this author Bertrand Tombal More articles by this author Jean-Christophe Eymard More articles by this author Johann De Bono More articles by this author Daniel Castellano More articles by this author Christian Wülfing More articles by this author Michail Liontos More articles by this author Joan Carles More articles by this author Roberto Iacovelli More articles by this author Bohuslav Melichar More articles by this author Ásgerður Sverrisdóttir More articles by this author Christine Theodore More articles by this author Susan Feyerabend More articles by this author Carole Helissey More articles by this author Ayse Ozatilgan More articles by this author Christine Geffriaud-Ricouard More articles by this author Ronald de Wit More articles by this author Expand All Advertisement PDF downloadLoading ...

5017 Background: Docetaxel and cabazitaxel represent now the standard of care in men with mCRPC with similar efficacy reported in metastatic first-line setting in the FIRSTANA phase 3 trial. We assessed patients’ preference between the two taxanes. Methods: Patients with taxane-naïve mCRPC were randomized in a 1:1 ratio to receive either docetaxel 75mg/m2/q3w x 4 followed by cabazitaxel 25mg/m2/q3w x 4 (DO-CA), or the reverse sequence (CA-DO). Randomization was stratified based on prior next generation AR axis inhibitors use. The primary endpoint was patient preference between taxanes, as assessed by questionnaires in patients who had received at least one cycle of each taxane and who had not experienced a progression while on the first taxane. Results: From June 2014 to October 2016, 195 men were randomized in 17 centers. After adjusting for the treatment period effect, more patients preferred cabazitaxel (43%) vs docetaxel (27%) (p < 0.004); 30% had no preference between taxanes. Fatigue, patient-defined quality of life, hair loss, and pain were the most common factors influencing patient preference. Febrile neutropenia was experienced by 5 (7.1%) men treated with cabazitaxel during the first period who received G-CSF and by 2 (7.1%) of those who did not. No febrile neutropenia was reported with docetaxel in both arms and with cabazitaxel during the 2nd period, irrespectively of the use of G-CSF. The incidence of diarrhea during the first 3-month period was slightly reduced with G-CSF use in men receiving cabazitaxel (32.1% vs 24.3%) but not in those receiving docetaxel (23.8% vs 25%). The median progression-free survival was 9.81 in the DO-CA arm and 9.33 months in the CA-DO arm. The median overall survival was also similar in the two groups (22.64 in the DO-CA arm and 20.73 months in the CA-DO arm. Conclusions: Although cabazitaxel and docetaxel have similar efficacy when used as first-line in mCRPC men, more patients prefer cabazitaxel. Clinical trial information: NCT02044354.

A randomized trial involving patients with metastatic prostate cancer whose disease progressed after receipt of docetaxel and hormonal therapy showed that cabazitaxel was superior to an androgen-signaling-targeted agent in extending imaging-based progression-free survival, overall survival, and PSA response. Background The efficacy and safety of cabazitaxel, as compared with an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel and had progression within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) are unclear. Methods We randomly assigned, in a 1:1 ratio, patients who had previously received docetaxel and an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide) to receive cabazitaxel (at a dose of 25 mg per square meter of body-surface area intravenously every 3 weeks, plus prednisone daily and granulocyte colony-stimulating factor) or the other androgen-signaling-targeted inhibitor (either 1000 mg of abiraterone plus prednisone daily or 160 mg of enzalutamide daily). The primary end point was imaging-based progression-free survival. Secondary end points of survival, response, and safety were assessed. Results A total of 255 patients underwent randomization. After a median follow-up of 9.2 months, imaging-based progression or death was reported in 95 of 129 patients (73.6%) in the cabazitaxel group, as compared with 101 of 126 patients (80.2%) in the group that received an androgen-signaling-targeted inhibitor (hazard ratio, 0.54; 95% confidence interval [CI], 0.40 to 0.73; P<0.001). The median imaging-based progression-free survival was 8.0 months with cabazitaxel and 3.7 months with the androgen-signaling-targeted inhibitor. The median overall survival was 13.6 months with cabazitaxel and 11.0 months with the androgen-signaling-targeted inhibitor (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.89; P=0.008). The median progression-free survival was 4.4 months with cabazitaxel and 2.7 months with an androgen-signaling-targeted inhibitor (hazard ratio for progression or death, 0.52; 95% CI, 0.40 to 0.68; P<0.001), a prostate-specific antigen response occurred in 35.7% and 13.5% of the patients, respectively (P<0.001), and tumor response was noted in 36.5% and 11.5% (P=0.004). Adverse events of grade 3 or higher occurred in 56.3% of patients receiving cabazitaxel and in 52.4% of those receiving an androgen-signaling-targeted inhibitor. No new safety signals were observed. Conclusions Cabazitaxel significantly improved a number of clinical outcomes, as compared with the androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling-targeted agent (abiraterone or enzalutamide). (Funded by Sanofi; CARD ClinicalTrials.gov number, .)

Background Taxanes (docetaxel [DOC], CBZ) and androgen receptor-targeted therapies (ARTs; ABI, ENZ) are standard of care in mCRPC. The optimal treatment sequence is unknown. CARD (NCT02485691) compared CBZ vs ABI or ENZ in patients with mCRPC previously treated with DOC and the alternative ART. Methods Patients with mCRPC previously treated with ≥ 3 cycles of DOC and progressing ≤ 12 months (mo) on an alternative ART, in any order, were randomized 1:1 to CBZ (25 mg/m2 IV Q3W + prednisone + G-CSF) vs ABI (1000 mg PO + prednisone) or ENZ (160 mg PO). Randomization was stratified by ECOG PS (0/1 vs 2), time to progression on prior ART (≤ 6 vs 6–12 mo) and ART timing (before vs after DOC). Primary endpoint was radiographic PFS (rPFS), with 196 rPFS events needed to test HR 0.67 for CBZ (80% power, 2-sided alpha 0.05). Secondary efficacy endpoints and safety were assessed. Results Overall, 255 patients (median age 70, 31.0% ≥ 75 yrs) were randomized. Median number of cycles was higher for CBZ vs ART (7 vs 4). rPFS was significantly improved with CBZ vs ART (median 8.0 vs 3.7 mo; HR 0.54; 95% CI 0.40–0.73; p Conclusions CBZ significantly improved clinically important patient outcomes including rPFS and OS vs ART in patients with mCRPC previously treated with DOC and an alternative ART. CBZ should be the preferred option in this setting. Sanofi funded. Clinical trial identification NCT02485691. Editorial acknowledgement Editorial support was provided by Amber Wood, Danielle Lindley and Tina Wasmeier of MediTech Media and funded by Sanofi. Legal entity responsible for the study Sanofi. Funding Sanofi. Disclosure R. de Wit: Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory Boards and speaker fees: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory Boards and speaker fees: Janssen; Advisory / Consultancy, Research grant / Funding (institution), Advisory Boards and institutional grants: Sanofi; Advisory / Consultancy, Research grant / Funding (self), Advisory Boards and institutional grants: Merck; Advisory / Consultancy, Research grant / Funding (institution), Advisory Boards and institutional grants: Bayer; Advisory / Consultancy, Research grant / Funding (self), Advisory Boards and institutional grants: Clovis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche. G. Kramer: Honoraria (self), Personal fess: Sanofi, Astellas, Takeda, Bayer, Janssen, Novartis, Ipsen, AstraZeneca; Research grant / Funding (self), Grant: Sanofi, Bayer. J. Eymard: Advisory / Consultancy, Board participation for Sanofi Aventis: Sanofi Aventis. J.S. de Bono: Honoraria (self), Advisory / Consultancy: AstraZeneca ; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Astellas Pharma; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Genentech/Roche ; Honoraria (self), Advisory / Consultancy: Janssen Oncology; Honoraria (self), Advisory / Consultancy: Menarini Silicon Biosystems; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Sierra Oncology; Honoraria (self): Bioexcell; Advisory / Consultancy: Bayer; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Celgene; Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: Genmab; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: Orion Pharma GmbH; Advisory / Consultancy: Eisai, BioXCel therapeutics. C.N. Sternberg: Honoraria (self): Janssen; Honoraria (self): AstraZeneca; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self): Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy: Pfizer; Honoraria (institution), Research grant / Funding (institution): Roche-Genentech, Bayer, Sanofi Genzyme, Janssen, Medivation, Exelixis. K. Fizazi: Honoraria (institution), Advisory / Consultancy: Amgen; Honoraria (institution), Advisory / Consultancy: Astellas; Honoraria (institution), Advisory / Consultancy: Astrazeneca; Honoraria (institution), Advisory / Consultancy: AAA; Honoraria (institution), Advisory / Consultancy: Bayer; Honoraria (institution), Advisory / Consultancy: Curevac; Honoraria (institution), Advisory / Consultancy: Essa; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution), Advisory / Consultancy: Orion; Honoraria (institution), Advisory / Consultancy: Sanofi. B. Tombal: Research grant / Funding (self): Astellas; Research grant / Funding (self): Janssen; Research grant / Funding (self), Non-remunerated activity/ies: Sanofi-Genzyme; Research grant / Funding (self): Amgen; Research grant / Funding (self): Ferring. A. Bamias: Honoraria (self): Astellas; Honoraria (self): Sanofi; Research grant / Funding (self): Janssen. J. Carles: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Johnson and Johnson; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas Pharma; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Speaker Bureau / Expert testimony: Asofarma. R. Iacovelli: Honoraria (self): Sanofi; Honoraria (self): Janssen; Honoraria (self): Pfizer; Honoraria (self): IPSEN; Honoraria (self): Novartis; Honoraria (self): BMS; Honoraria (self): MSD. B. Melichar: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer. A. Ozatilgan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Sanofi. C. Geffriaud-Ricouard: Full / Part-time employment: Sanofi. D. Castellano: Honoraria (self), Personal fees: Pfizer; Honoraria (self), Personal fees: Roche; Honoraria (self), Personal fees: Sanofi; Honoraria (self), Personal fees: Janssen; Honoraria (self), Personal fees: Astellas; Honoraria (self), Personal fees: Bayer; Honoraria (self), Personal fees: BMS; Honoraria (self), Personal fees: MSD; Honoraria (self), Personal fees: Merck Serono; Honoraria (self), Personal fees: Pierre Fabre; Honoraria (self), Personal fees: AstraZeneca; Honoraria (self), Personal fees: Lilly. All other authors have declared no conflicts of interest.

BACKGROUND:The impact of cisplatin use on long-term survival of unselected patients with advanced urinary tract cancer (aUTC) has not been adequately investigated. We used a multinational database to study long-term survival and the impact of treatment type in unselected patients with aUTC. MATERIALS AND METHODS:A total of 1,333 patients with aUTC (cT4bN0M0, cTanyN+M0, cTanyNanyM+), transitional-cell, squamous, or adenocarcinoma histology who received systemic chemotherapy and had available survival data were selected. Long-term survival was defined as alive at 3 years following initiation of first-line chemotherapy. Conditional overall survival (COS) analysis was employed to study change in prognosis given time survived from initiation of first-line chemotherapy. RESULTS:Median follow-up was 31.7 months. The combination of cisplatin use and cisplatin eligibility accurately predicted long-term survival. Eligible patients treated with cisplatin conferred a 31.6% probability of 3-year survival (95% confidence interval [CI]: 25.1-38.3), and 2-year COS for patients surviving 3 years after initiation of cisplatin-based chemotherapy was 83% (95% CI: 59.7-93.5). The respective probabilities for patients who were ineligible for cisplatin or not treated with cisplatin despite eligibility were 14% (95% CI: 10.8-17.6) and 49.3% (95% CI: 28.2-67.4). Two-year COS remained significantly different between these two groups up to 3 years after chemotherapy initiation. CONCLUSION:Cisplatin-based therapy was associated with the highest likelihood of long-term survival in patients with aUTC and should be used in patients who fulfill the established eligibility criteria. Novel therapies are necessary to increase long-term survival in cisplatin-ineligible patients. IMPLICATIONS FOR PRACTICE:Long-term, disease-free survival is possible in one in four eligible-for-cisplatin patients with advanced urinary tract cancer (aUTC) treated with cisplatin-based combination chemotherapy. Therefore, deviations from eligibility criteria should be avoided. Consolidation surgery should be considered in responders. These data provide benchmarks for the study of novel therapies in aUTC.