Karim Fizazi

LBA3 Background: Pts with newly diagnosed mHNPC, particularly with high-risk characteristics, have a poor prognosis. ADT+docetaxel showed improved outcomes in mHNPC, but many pts are not candidates for docetaxel and may benefit from alternative therapy. AA+P is indicated for metastatic castration-resistant prostate cancer pts. LATITUDE evaluates clinical benefit of early intervention with AA+P added to ADT in newly diagnosed, high-risk mHNPC pts. Methods: 1199 pts with newly diagnosed (≤ 3 mos prior to randomization) mHNPC (ECOG PS 0-2) with ≥ 2 of 3 risk factors (Gleason ≥ 8, ≥ 3 bone lesions, measurable visceral metastases) were randomized 1:1 to ADT+AA (1 g QD) + P (5 mg QD) or ADT+PBOs of AA and P. Co-primary end points were overall survival (OS) and radiographic progression-free survival (rPFS). One rPFS (~565 events), 2 interim, and 1 final OS analyses (~426, ~554, and ~852 events) were planned. Results: At this first interim analysis (median follow-up of 30.4 mos; 406 deaths [48%]; 593 rPFS events), OS, rPFS, and all secondary end points significantly favored ADT+AA+P (Table). The IDMC unanimously recommended unblinding the study and crossing pts to ADT+AA+P. Grade 3/4 adverse events (ADT+AA+P vs ADT+PBOs) (%): hypertension (20.3 vs 10.0); hypokalemia (10.4 vs 1.3); increased ALT (5.5 vs 1.3) or AST (4.4 vs 1.5). Conclusions: Early use of AA+P added to ADT in pts with high-risk mHNPC yielded significantly improved OS, rPFS, and all secondary end points vs ADT+PBOs alone. ADT+AA+P had a favorable risk/benefit ratio and supports early intervention with AA+P in newly diagnosed, high-risk mHNPC. Clinical trial information: NCT01715285. [Table: see text]

10069 Background: A substantial proportion of breast, colo-rectal and prostate cancer patients (pts) can expect long term disease free survival after their primary treatment. Among those, fatigue commonly persists after diagnosis (dx) and can be debilitating. In this study, we evaluated the incidence of fatigue 2 years (y) after cancer dx and its association with health behaviors. Methods: We used a French population based cross-sectional study, which included a representative sample of pts from 12 cancer types (VICAN2). VICAN2 surveyed 4347 pts 2 y after dx. There is a 99% completion rate of fatigue related questions. For this study, we included 2017 pts with breast (1237), colo-rectal (348) and prostate (432) cancer without evidence of metastases at dx or relapse 2y after dx and with fatigue information. Severe fatigue was defined as average score of EORTC QLQC30 fatigue subscale ≥40 at 2y after dx. There were aOR] for severe fatigue, 95% confidence interval [95% CI]: 0.97, 0.96-0.98), gender (aOR, 95 CI male vs. female: 0.5, 0.3-0.8), comorbidities (aOR, 95 CI yes vs. no: 2.0, 1.6-2.4) and treatment type (aOR, 95 CI radiation vs. no: 1.5, 1.1-2.0). Conclusions: Fatigue continues to be a substantial problem for cancer survivors 2 y after dx. Some factors that may contribute to persistent fatigue (health behaviors) may be amenable to interventions.

TPS5092 Background: Androgen deprivation therapy (ADT) ± docetaxel is recommended first-line therapy for mHSPC, but most patients progress to castration-resistant PC (CRPC). BAY-1841788 (ODM-201) is an investigational oral androgen receptor (AR) antagonist that has a unique chemical structure designed to block the growth of cancer cells through binding to the AR with high affinity and inhibiting the receptor function. In preclinical studies, ODM-201 and its main circulating metabolite are active also in known AR mutants (eg, W742L, F877L), and have been found to have negligible blood-brain barrier penetration. In the phase 1 ARAFOR and phase 1/2 ARADES trials, ODM-201 had antitumor activity and was well tolerated in men with mCRPC (Massard et al. Eur Urol. 2016;69:834‒840; Fizazi et al. Lancet Oncol. 2014;15:975‒985). Given this promising activity in mCRPC, the ARASENS trial is evaluating ODM-201 plus standard ADT + docetaxel in men with metastatic disease (mHSPC). Methods: This international, randomized, double-blind, placebo-controlled, phase 3 trial (NCT02799602) is being conducted in 23 countries. ~1300 men with newly diagnosed mHSPC will be randomized 1:1 to either ODM-201 600 mg twice daily (2×300 mg tablets) orally with food or placebo, both with ADT + docetaxel (6 cycles after randomization), and stratified by extent of disease and alkaline phosphatase levels. Key inclusion criteria are histologically or cytologically confirmed PC with documented metastases, started ADT ± first-generation anti-androgen therapy ≤12 weeks before randomization, and Eastern Cooperative Oncology Group performance status 0 or 1. The primary objective is to show superior overall survival with ODM-201 vs placebo, both with ADT + docetaxel. Secondary end points include time to CRPC, initiation of subsequent anticancer therapy, symptomatic skeletal event-free survival (SSE-FS), time to first SSE, initiation of opioid use, pain progression, and worsening of physical symptoms, all measured at 12-week intervals. Safety will be assessed by adverse events. The trial is open for enrollment; first patient first visit was in November 2016 and > 10 sites are open for recruitment and enrolling patients. Clinical trial information: NCT02799602.

4554 Background: We conducted a national phase II multicenter trial that aimed at evaluating the efficacy and tolerance of Paclitaxel plus Ifosfamide followed by high-dose carboplatin plus etoposide treatment (TICE) in previously treated germ cell tumors. The particularity of our study (in comparison with the standard protocol [Motzer RJ, et al. J Clin Oncol 2000 Mar; 18(6): 1173-1180.]) is that the carboplatin dose was individualized for each patient according to therapeutic drug monitoring (TDM) in order to reach the target AUC of 24 mg.min/ml over 3 days. Methods: In total, 89 patients were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/ml over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC and the intra- and inter-cycle clearance variability. Secondly, a population pharmacokinetic analysis was also performed on 59 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future patients treated with the TICE protocol. The performance of this new equation was then prospectively evaluated on the other 30 patients along with different methods of carboplatin clearance prediction. Results: TDM allowed us to control the carboplatin exposure with a mean actual AUC of 24.5 mg.min/ml (22.2 and 28.0 for 5^th and 95^thpercentile respectively) per cycle. We observed a modest but significant decrease of carboplatin clearance over cycles (median value of change of -11.8% from cycle 1 to cycle 3, maximum value of -36%). The new covariate equation allows unbiased and more accurate prediction of carboplatin clearance in the prospective validation cohort compared to other equations. Conclusions: Carboplatin TDM allowed the target AUC to be accurately reached and thereby avoid over- or under-exposure. We propose a new equation to predict carboplatin clearance more adapted to these particular patients (young males) that could be used as an alternative if the TDM cannot be organized. Clinical trial information: 2008-005068-14.

5012 Background: Combining docetaxel to androgen deprivation therapy (ADT) improves survival in metastatic castration-sensitive prostate cancer (CSPC) (Vale C, Lancet Oncol 2016; 17: 243-56) and it also improves relapse-free survival (RFS) in high-risk localized CSPC (Fizazi K, Lancet Oncol 2015; 16: 787-94). However it is unlikely that all patients (pts) derive a benefit from docetaxel treatment and identifying predictive biomarkers remains a major unmet need. A subset of prostate cancers contains TMPRSS2-ERG gene fusions leading to ERG overexpression. Methods: Pre-treatment prostate core biopsies were collected from 255/413 pts and 79/385 pts enrolled respectively in the GETUG 12 and GETUG 15 (Gravis G, Eur Urol 2016; 70: 256-62) phase 3 trials testing early docetaxel in high-risk localized and metastatic CSPC. ERG, PTEN, Ki67 and Rb expression was assessed using immunohistochemistry. RFS curves were compared using the Logrank test. Results: The median age was 63 years (46-77) and 62 years (49-76) in GETUG 12 and GETUG 15. ERG staining was positive in 88/191 (46%) and 33/79 (42%) pts with available tissue, respectively. In GETUG 12, docetaxel-based chemotherapy was associated with improved RFS in pts with ERG+ expression (HR = 0.55 [0.29-1.03]; 6-year RFS : 80% ADT+docetaxel vs 68% ADT alone), but not in pts with ERG- (HR = 1.10 [0.66-1.85]; 6-year RFS 55% ADT+docetaxel vs 60% ADT alone), interaction test: p = 0.02. Similar findings were observed in GETUG 15, which was used as a validation set: the median RFS was 10.7 (6.5-14.3) and 18.8 (9.8-41) months in pts with ERG+ cancers receiving ADT alone and ADT+docetaxel, and 10.6 (4.8-25.3) and 13.2 (9.4-24) months in pts with ERG- cancers. In contrast, no difference in patient outcome by docetaxel treatment was observed by PTEN, Ki67 and Rb expression. Conclusions: Docetaxel-related benefit in men with CSPC is predicted by ERG expression. This biomarker may help better select pts for docetaxel treatment.

5007 Background: Radiographic progression and overall survival (OS) are the traditional clinical benefit measures for mCRPC trials. Reliable indicators of response that occur early are a critical unmet need in practice and clinical research. We explored a week 13 CTC and prostate-specific antigen (PSA) endpoint relative to baseline in 5 prospective randomized phase 3 registration trials that enrolled 5912 pts. OS was the primary endpoint. Methods: CTC number (CellSearch) and PSA values in patients who survived at least 13 weeks were evaluated as response endpoints in COU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4 and COMET-1. Pts with missing values at week 13 were considered non-responders. The endpoints considered are shown in Table 1. Results: The discriminatory strength of the response endpoints with respect to OS was estimated using the weighted c-index. To summarize discrimination results for each measure, the mean and the standard deviation based on the weighted c-indices from the 5 studies were computed. Conclusions: CTC0 and CTC conversion endpoints had the highest discriminatory power for OS relative to the % decline in CTC or PSA endpoints. The percent of pts eligible and evaluable for the CTC0 endpoint was significantly higher than the conversion endpoint, 75% vs. 51%, respectively. These two absolute measures of CTC can be considered meaningful response indicators in mCRPC clinical trials. [Table: see text] [Table: see text]

148 Background: Molecular characterization of metastatic castration resistant prostate cancer (mCRPC) is limited by tumor tissue availability. The analysis of circulating tumor cells (CTC) offers an attractive noninvasive surrogate option to analyze molecular alterations. We report whole exome sequencing (WES) of CTCs at the single cell level in mCRPC patients. Methods: Blood samples were drawn from 11 enzalutamide or abiraterone pre-treated mCRPC patients enrolled in the clinical program MOSCATO (NCT02613962). CTC enrichment, immunofluorescent detection and single cell isolation were performed using three methods (ISET filtration, CellSearch and the VyCap puncher system and RosetteSep enrichment) to obtain pools of 1-10 CTCs with distinct epithelial or mesenchymal phenotypes. After Whole Genome Amplification (WGA), WES was performed on the Illumina HiSeq 2000 platform. GATK Haplotype Caller enabled identification of germline polymorphisms from each patient in normal DNA, metastatic sample and CTCs in order to consider WGA induced bias. The detection of sSNV in tumor biopsies and CTCs was assessed with Mutect and IndelGenotyper respectively. Results: 189 WGA of CTC pools were performed. 34 pools of phenotypically different CTCs from 7 patients were selected and sequenced. Mean coverage of 51% was obtained at a sequencing depth of 10X. Allelic drop out was lower for CTC pools containing 5-10 cells. 17/34 (50%) CTC samples had shared sSNV with the paired tumor sample (range 0.35%-68%) Epithelial CTCs had more shared sSNV with metastatic biopsies than CTCs of other phenotypes but shared sSNV were also detected in large non epithelial CTC pointing out a high level of genetic heterogeneity between CTC. Overall, 89 deleterious protein-coding mutations were found only in pools of CTC, including mutations affecting oncogenic drivers such as MAPK1, HSP90AB1 or KDM5B. Conclusions: We present single cell WES of CTCs harboring distinct phenotypes. The detection of shared sSNV between CTC pools and corresponding biopsy could validate the use of CTCs as a liquid biopsy. The finding of sSNV specific to CTCs could offer additional data on tumor heterogeneity.

463 Background: Bone metastases (BMs) are associated with significant morbidity and shorter survival in metastatic renal cell carcinoma (mRCC). Our purpose was to identify prognostic factors for mRCC patients (pts) with BMs. Methods: Data from mRCC pts with BMs, treated at Gustave Roussy between April 1992 and March 2016, were retrospectively collected. Age, sex, ECOG-Performance Status (PS), Memorial Sloan-Kettering Cancer Center (MSKCC) score, histology, number and site of BMs, concomitant metastases (presence and sites), therapy for BMs (radical resection or palliative surgery, radiotherapy, other local and systemic treatments), time to BMs, and outcome were analyzed. Synchronous solitary bone metastasis (SSBM) was defined as a single bone metastasis without concomitant visceral lesions at the initial diagnosis of RCC. Overall survival (OS) was calculated from the date of BMs diagnosis to death or last follow-up using Kaplan-Maier method and modelled with Cox-regression analysis. Results: Three hundred pts were identified. Median time to BMs was 32.4 months (range 0–324 months). In 64 pts (21%), bone was the only metastatic site and 22 of them (7%) had a SSBM; 236 pts (79%) had concomitant metastases in other sites. Median OS was 23.22 months. SSBM pts had better OS then those with concomitant metastases (40 vs. 20 months; p<0.001). At univariate analysis, number of BMs (p<0.0001), spinal column as site of BMs (p<0.005), concomitant metastases (p<0.0001), Fuhrman grade (p<0.001), non-clear cell histology (p<0.003), and MSKCC score (p1) and radical resection are prognostic factors. Additionally, in presence of solitary bone metastasis without other concomitant metastases at the initial diagnosis of RCC, bone surgery should be considered to achieve local tumor control and increase survival.

420 Background: Late relapse in patients with germ cell tumors (GCT) are rare events. As there is no consensus for follow-up (FU) protocols, it is unclear if shorter duration of CT scanning is safe while reducing unnecessary exposure to radiation. Methods: At the completion of their treatment, all patients with Stage I, metastatic good or intermediate prognosis seminoma and non-seminoma (NSGT) underwent physical exam, serum tumor markers and imaging at regular intervals. We retrospectively identified 2 groups of patients with different FU strategies: those with regular CT scan of the chest, abdomen and pelvis for 3 years or less, then followed by abdomino-pelvic ultrasound (Group 1); and those with CT scanning continued beyond 3 years (Group 2). Results: Between December 1997 and March 2016, 203 patients were included: 80 (39.4%) in Group 1 and 123 (60.6%) in Group 2. The mean duration of FU was 6.7 ± 2.4 years in Group 1 and 8.1 ± 2.5 years in Group 2 (p < 0.001). After year 3 the median number of abdomino-pelvic ultrasound in Group 1 was 5 (4-6) and the median number of CT scanning in Group 2 was 6 (5-8). Five (2.4%) relapses were identified: 1 in Group 1 and 4 in Group 2. Relapse was revealed by symptoms in 2 patients with NSGT (1 in each group) who had been lost for FU. Three patients underwent local treatment (2 surgeries for teratoma relapses and 1 radiotherapy for seminoma relapse) and are still disease-free. International prognostic factors score was low and intermediate for the first 2 patients, very low for seminoma relapse and low for teratoma relapses. Conclusions: Patient follow-up by regular abdomino-pelvic ultrasound instead of CT scan appears a feasible alternative after the third year in patients with GCT, with no excess risk of incurable relapses. Prospective validation is required.

401 Background: HDCT is a valid option of treatment for relapsed advanced GCTs pts. The results of the TICE regimen as salvage therapy in poor risk pts demonstrated a 50% complete response (CR) but with very high variability of measured carboplatin area under the curve (AUC) (between 10.9-36.7 for target AUC = 24 mg.min/mL). We initiated a phase II trial of TICE with therapeutic drug monitoring (TDM) for individual carboplatin dosing in order to target the 3-day AUC to 24 mg/min/mL. Methods: Were included pts with unfavorable relapsed GCTs , secondarily classified according to the International Prognostic Factors Study Group. Pts were treated according the TICE regimen with two cycles combining paclitaxel and ifosfamide followed by three cycles HDCT: carboplatin plus etoposide with stem cell support. Carboplatin dose was adapted on day 3 based on carboplatin clearance (Cl) at day 1, in order to reach the target AUC. The primary endpoint was the CR rate (cCR sCR pCR). A Simon Minimax design was performed using the following hypothesis: p0 = 50%, p1 = 65 α = 5%, β = 10%. Results: Between 03/2009 and 11/2015 101 pts were accrued, 60 pts were treated in first relapse (34 classified as high and very high-risk) and 41 in 2^ndor more relapse. 72 pts (71%) received the whole treatment, 12 pts (10%) did not receive any cycle of HDCT. 29pts (26%) stopped treatment earlier, 8 for toxicity. Three pts died on treatment. 35/79 (44.3%) evaluable pts achieved a CR. 19 pts (24%) presented a PRm-. The mean observed carboplatin AUC was 24.5 mg.min/mL (between 18.9 and 28.8) at C1.Following TDM, the modification of the total carboplatin dose during C1 was comprised between -33% and +44%, showing the benefit of TDM in comparison with individual dosing based only on carboplatin Cl predicted according to patient’s renal characteristics. Conclusions: The CR rate observed in this very poor prognosis population was 44.3% and 69.6% CR + PRm-. Carboplatin dose individualization based on TDM allowed to reach more accurately the target AUC compared to previous reports. Clinical trial information: NCT00864318.