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471 Background: In the phase 3 JAVELIN Bladder 100 trial, avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) vs BSC alone in pts with aUC that had not progressed with 1L platinum-based chemotherapy (CTx). The JAVELIN Bladder regimen is now standard of care with level 1 evidence in international treatment guidelines. The AVENANCE study (NCT04822350), is investigating the efficacy and safety of avelumab 1L maintenance in a real-world population of pts with aUC in France. Data from the full analysis set are reported for the first time. Methods: In this ongoing, noninterventional, ambispective study, eligible pts have locally advanced or metastatic UC that has not progressed with 1L platinum-based CTx and previous, ongoing, or planned avelumab 1L maintenance treatment. The primary endpoint is OS from start of avelumab; secondary endpoints include progression-free survival (PFS), duration of treatment (DOT), and safety. Results: 591 pts received avelumab. At data cutoff (July 31, 2022), median follow-up was 12.0 mo (95% CI, 10.9-12.9). Median age was 73.1 y (IQR, 67.0-78.1). At start of 1L CTx (excluding pts with missing data), disease stage was metastatic in 524 pts (90.5%; visceral metastases in 426 [81.5%]) and locally advanced in 54 (9.3%). ECOG PS was 0-1 in 407 pts (85.3%) and 2-3 in 69 (14.5%). Tumor histology was pure UC in 528 pts (91.8%) and UC with variant or pure variant in 47 (8.2%). 1L CTx was gemcitabine + carboplatin (GemCarbo), gemcitabine + cisplatin (GemCis), dose-dense methotrexate + vinblastine + adriamycin + cisplatin (DD-MVAC), and other in 353 (61.0%), 170 (29.4%), 28 (4.8%), and 28 (4.8%) pts, respectively. Median number of cycles was 5 (range, 1-10). Median DOT with avelumab was 5.8 mo (95% CI, 5.2-7.0); 241 pts (40.8%) remained on treatment at data cutoff. The most common reasons for treatment discontinuation were disease progression (74.1% [n=258]), death (11.5% [n=40]), and adverse events ([AEs] 10.3% [n=36]). Median OS from start of avelumab was 18.4 mo (95% CI, 15.4-not estimable [NE]), the 12-month OS rate was 64.8% (95% CI, 60.0%-69.1%), and median PFS was 5.7 mo (95% CI, 5.3-7.0). In pts who had received GemCarbo, GemCis, or DD-MVAC, median OS (95% CI) was 16.2 mo (13.4-NE), not reached (NR; 18.1-NE), and NR (15.2-NE), respectively. Subgroups analyses will be presented. 218 pts received subsequent 2L, including CTx, antibody-drug conjugates, immunotherapy, and other in 186 (85.3%), 22 (10.1%), 6 (2.8%), and 4 (1.8%) pts, respectively. Any-grade treatment-related AEs (TRAEs) occurred in 217 pts (36.7%), including serious TRAEs in 29 (4.9%). Conclusions: Real-world data for avelumab 1L maintenance in pts with aUC from AVENANCE support the findings of JAVELIN Bladder 100 and confirm the clinical activity and acceptable safety profile of avelumab in a heterogeneous population. Clinical trial information: NCT04822350 .

11520 Background: AcSé Pembrolizumab is a Phase 2, non-randomized parallel arms, open-label, multicentric study from Unicancer investigating the efficacy and safety of pembrolizumab monotherapy in different cohorts of patients with rare cancers (NCT03012620). Here we report the results of pembrolizumab in the rare sarcoma cohort. Methods: Selected histotypes were all rare sarcomas patients (pts) (incidence < 0.2/100,000/year). Main inclusion criteria were age > 18, ECOG PS≤1 and advanced or metastatic disease resistant to standard treatment. Patients received pembrolizumab 200 mg IV as a 30-minute infusion on Day 1 of every 21-day cycle for a maximum of 2 years. The primary endpoint was the confirmed objective response rate according to RECIST v1.1 at 12 weeks. Secondary endpoints included clinical benefit rate, duration of response, progression-free survival (PFS), overall survival (OS), and safety. Five groups of pts were distinguished, namely chordoma, alveolar soft-part sarcoma (ASPS), desmoplastic small round cell tumor (DSRCT), smarca4 deficient malignant rhabdoid tumor (SMRT), and other histotypes. Results: 98 patients including 34 with chordoma, 14 ASPS, 11 SMRT, 8 DSCRT and 31 with other histotypes, were included from July 2017 to December 2020. The median number of cycles was 5 (range, 1 to 35) with 78 (79.6%) patients who discontinued the trial after a median of 4 cycles. There were 6 (7.3%) partial response (PR) at 12 weeks. The best response was CR in 1 patient (1%), PR in 14 patients (14.3%), and stable disease (SD) in 33 (33.7%). Median duration of response was 8.2 months [IQR, 4.1 to 9.0]. The occurrence of best response depended on the histotype, with 3 (8.8%) responses in chordoma, 7 (50%) in ASPS, 3 (27%) in SMRT, 1 (12.5%) in DSCRT and 1 (3.2%) in other histotypes (p = 0.0011). At the data cut off, median PFS was 2.75 months, and median OS was 19.7 months on the overall population. Outcomes differed according to the histotype group, with the 12 months PFS rates at 31.2% (chordoma), 35.7% (ASPS), 18.2% (SMRT), 0% (DSCRT) and 3.3% (other), respectively (p < 0.0001), and median PFS at 6.6 (chordoma), 7.5 (ASPS), 1.1 (SMRT), 2.1 (DSCRT) and 2.1 months (other), while 1-year OS rates were 76.6% (chordoma), 85.7% (ASPS), 36.4% (SMRT), 17.5% (DSCRT) and 42.9% (other) with median OS only reached for SMRT (2.4 months), DSRCT (10 months), and the other histotype group (7.1 months) (p = 0.004). The side effect profile of pembrolizumab was similar to other tumor type. Conclusions: Pembrolizumab is safe and well tolerate in this pop od STS pts, AcSé study reports high levels response rate and prolonged activity in selected subtypes of rare sarcomas. Clinical trial information: NCT03012620.

5046 Background: Darolutamide (Daro) and enzamutamide (Enza) are both next generation androgen receptor inhibitors with demonstrated activity in men with CRPC. Although both agents are associated with survival improvement, their toxicity profiles are different. To help decipher whether this may impact on patient preference, we designed the ODENZA trial. Methods: ODENZA is a prospective, randomized, open-label, multicenter, cross-over, phase II trial of preference between Daro and Enza in men with asymptomatic or mildly symptomatic metastatic CRPC. Patients were randomized 1/1 to receive Daro 1200 mg/d for 12 weeks followed by Enza 160 mg/d for 12 weeks (Daro-Enza arm) or the reverse sequence (Enza-Daro arm). In both arms, the second treatment was given in absence of evidence of cancer progression at week 12. The primary endpoint was patient preference between the two drugs, as assessed by a questionnaire at week 24. The Prescott's test was used to determine treatment preference in patients fullfilling pre planned criteria (exposure to both treatments, no progression at week 12, and completion of the preference questionnaire). A p-value greater than 0.05 indicates that there is no difference in preference between treatments. Stratification factors were performance status and prior taxane for mCSPC. After week 24, patients went on to an extension period during which they received the chosen treatment until progression or toxicity. The main secondary objectives included reasons for preference, response at week 12, cognitive assessment, and toxicity. Results: Overall 249 pts were randomized, median age 72y (68; 79), ECOG PS 0 (56%), prior taxanes (22%). Two hundred pts fulfilled the pre-planned criteria for evaluation of the preference primary endpoint : 97 (48.5% [41.3;55.7]), 80 (40.0% [33.0;47.0]), and 23 (11.5% [6.8;16.2]) chose Daro, Enza, and had no preference, respectively (unilateral p-value of 0.92). After preference assessment, 186 patients entered the extension period: 103 (55.4%) and 83 (44.6%) received Daro and Enza respectively. The most common factors influencing patient preference all numerically favored Daro over Enza, without significant differences were: less fatigue (44% vs 29%), ease of taking the medication (37% vs 31%), better quality of life (36% vs 28%), ability to be more active (26% vs 15%), ability to concentrate (22% vs 15%) and less falls (6% vs 3%). A PSA50 response was achieved in 76.2% and 83.9% at week 12 with Daro and Enza respectively (p = 0.13). Fatigue was the most frequently reported all grade adverse event at week 12, in 21% and 36% with Daro and Enza, respectively. Conclusions: More patients with early mCRPC preferred Daro over Enza, although the difference did not reach significance, with fatigue as the key influencing factor. Clinical trial information: NCT03314324.

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]

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]

TPS770 Background: Cabozantinib, an inhibitor of multiple receptor tyrosine kinases including VEGF receptor 2, and MET and AXL receptors, is approved for the treatment of aRCC in the USA and, in Europe, in treatment-naïve patients with intermediate or poor risk, as well as following VEGF-targeted therapy. The METEOR trial investigated cabozantinib as second-line (2L) or later-line therapy and showed improved progression-free survival (PFS), objective response rate and overall survival vs everolimus. Adverse events (AEs) associated with cabozantinib were generally manageable in METEOR; dose interruptions and reductions occurred in 70% and 60% of patients, respectively. Here we present the design of the CASSIOPE study which aims to assess the real-life use of cabozantinib as 2L or third- or later-line (≥ 3L) therapy for aRCC. Methods: CASSIOPE is an ongoing, European, prospective, non-interventional study in adults with aRCC who have received ≥ 1 prior VEGF-targeted therapy and are initiating cabozantinib as 2L or ≥ 3L therapy according to Summary of Product Characteristics. The primary endpoint is the proportion of patients with dose modifications (interruption, reduction or discontinuation) due to AEs. Secondary endpoints include additional drug utilization parameters, effectiveness (overall best response, PFS), and healthcare resource utilization associated with managing treatment-related AEs. Overall, 680 patients (340 on 2L therapy; 340 on ≥ 3L therapy) will be enrolled to assess the 2-sided 95% confidence interval of the primary endpoint with a precision of ± 5%, assuming a 75% dose modification rate and ≤15% of starting doses lower than 60 mg. Visits will be based on the site's clinical practice, with a maximum follow-up of 12 months after treatment initiation, even if treatment is continued. Data collection started in April 2018. As of 9 October 2019, 336 patients have been enrolled. The overall study duration is expected to be 36 months. An interim analysis is planned when ≥ 340 patients have completed ≥ 3 months follow-up from treatment initiation. The study is funded by Ipsen Pharma. Clinical trial information: NCT03419572; EUPAS19464.

189 Background: We previously reported that cancer pain was associated with a poor prognosis in mCRPC patients (pts) treated with docetaxel (D) ( Oudard, BJU Int 2009). Asymptomatic chemo-naive pts treated with novel androgen receptor targeted agent (H) have a greater overall survival (OS) than those with mild symptoms ( Miller, Eur Urol 2018). We thus investigated the impact on OS of progression type at initiation of first-, second- and third-line of LET in a large cohort of mCRPC pts (CATS registry) treated with D, cabazitaxel (C) and H. Methods: 669 consecutive mCRPC pts treated with 3 LETs (DCH, n= 158; DHC, n=456; HDC, n=55) were retrospectively reviewed. Type of progression: PSA alone, radiographic ± PSA, clinical ± PSA ± radiographic at initiation of each LET was evaluable in 661 pts. Clinical progression was defined by worsening of cancer-related pain or symptoms as per physician judgment. Results: Clinical progression at initiation of LET increased with the number of treatment lines and was consistently associated with a worse outcome. Clinical progression was associated with a significantly shorter duration of treatment with H but had no influence on duration of taxanes. Conclusions: In pts treated with 3 LTEs (D, C and H) clinical progression at sequence initiation is associated with a poor OS and a shorter duration of hormonal treatment. These data may help guide treatment decisions.[Table: see text]

Purpose Cross-talk between signal transduction pathways likely contributes to hormone resistance in metastatic breast cancer (mBC). Everolimus, an oral inhibitor of the mammalian target of rapamycin, has restored sensitivity in endocrine-resistance models and shown anticancer activity in early-phase mBC clinical trials. This analysis evaluated efficacy and safety of everolimus in combination with tamoxifen in patients with mBC resistant to aromatase inhibitors (AIs). Patients and Methods This open-label, phase II study randomly assigned postmenopausal women with hormone receptor–positive, human epidermal growth factor receptor 2–negative, AI-resistant mBC to tamoxifen 20 mg/d plus everolimus 10 mg/d (n = 54) or tamoxifen 20 mg/d alone (n = 57). Randomization was stratified by primary and secondary hormone resistance. Primary end point was clinical benefit rate (CBR), defined as the percentage of all patients with a complete or partial response or stable disease at 6 months. No formal statistical comparison between groups was planned. Results The 6-month CBR was 61% (95% CI, 47 to 74) with tamoxifen plus everolimus and 42% (95% CI, 29 to 56) with tamoxifen alone. Time to progression (TTP) increased from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus everolimus, corresponding to a 46% reduction in risk of progression with the combination (hazard ratio [HR], 0.54; 95% CI, 0.36 to 0.81). Risk of death was reduced by 55% with tamoxifen plus everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24 to 0.81). The main toxicities associated with tamoxifen plus everolimus were fatigue (72% v 53% with tamoxifen alone), stomatitis (56% v 7%), rash (44% v 7%), anorexia (43% v 18%), and diarrhea (39% v 11%). Conclusion This study suggests that tamoxifen plus everolimus increased CBR, TTP, and overall survival compared with tamoxifen alone in postmenopausal women with AI-resistant mBC.

TPS334Background: In recent years, the treatment of mCRPC has evolved and next-generation androgen receptor (AR)-axis targeting drugs (enzalutamide (ENZ), and abiraterone) have been approved and ar...

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]

5033 Background: Only 2 chemotherapies have shown an overall survival (OS) benefit in mCRPC: docetaxel (DOC) and CABA. In patients (pts) previously treated with a new hormonal therapy (NHT: enzalutamide or abiraterone), DOC and CABA, therapeutic options are limited. We previously reported some activity of DOC rechallenge in good responders to first-line DOC. We present here the results of a retrospective study evaluating the efficacy and safety of CABA rechallenge. Methods: Records of 70 mCRPC pts rechallenged with CABA were collected in 17 centers (France, Italy, UK, Austria). To be included, pts should have previously received DOC, NHT and CABA with a good response to CABA. Results: Of these 70 pts, 52 received DOC-NHT-CABA, 15 DOC-CABA-NHT and 3 NHT-DOC-CABA. At rechallenge, 83% had a high-volume disease (CHAARTED definition), 10% had visceral mets, 66% consumed narcotic analgesics, 68 % were ECOG 0-1 and median neutrophil/lymphocyte ratio (NLR) was 3.1. CABA was rechallenged for a median of 6 cycles (25 mg/m2 q3w, 59%; 20 mg/m2, 27%; 16 mg/m2q3w 11%) with prophylactic G-CSF in 47%. Median time from last CABA cycle was 8.6 months (mo). CABA rechallenge had an acceptable tolerability: 7 pts (10%) had grade 3-4 toxicity (neutropenia). Data on efficacy are reported in Table 1. Median progression-free survival (PFS) was 11.3 mo with DOC, 12 mo with NHT, 11.9 mo with first CABA (median 8 cycles), and 7.8 mo with CABA rechallenge. Median OS calculated from the first life-extending therapy was 59.9 mo (95% CI 47.8; 66.4). Conclusions: This retrospective cohort of heavily treated mCRPC pts suggests that CABA rechallenge has a good activity with a manageable toxicity. CABA rechallenge might be an option in heavily treated pts still fit to receive chemotherapy. [Table: see text]

e12592 Background: During last decade, therapeutic arsenal has expanded for metastatic breast cancer (mBC), but few data are available about mTNBC, a poor prognosis subtype. In 2014, UNICANCER (composed of 18 French Comprehensive Cancer Centers) launched the Epidemiological Strategy and Medical Economics (ESME) program to centralize real-world data. This base represents a great opportunity to update the outcomes and the treatment practice patterns of this population. Methods: The ESME-mBC database was built from information systems, treatment databases and patients’ electronic files including quality control processes. All pts who initiated treatment for mBC between 01-Jan-2008 and 31-Dec-2014 were selected. The primary objective of this study was to assess overall survival (OS) of mTNBC pts. TNBC status was defined as ER and PR < 10% in both primary and metastatic disease, as well as the absence of overexpression or amplification of HER2. The secondary objectives were to describe the characteristics of this population, clinical management (duration and sequence of treatments) and to evaluate the prognostic value of several clinical factors (age, distant disease free interval, location and number of metastatic sites) Results: Among 16703 pts in the ESME-mBC database, 2368 (14%) had mTNBC. Median OS over this time period was 14.8 months (95% CI 14-15.6). Median age at diagnosis of mBC was 57 years. For the pts who relapsed, median metastasis free interval was 24 months, while 25.5% of the pts were de novo metastatic. 61% of the pts presented visceral metastasis and 12% had cerebral metastasis as first metastatic site. The pattern of metastatic involvement (visceral and cerebral) and a short metastasis free interval ( < 24 months) were the most important prognostic factors in multivariate analysis. The description of treatment sequences (duration, prognostic value) will be presented. Conclusions: In this real-life setting database, mTNBC remain of poor prognosis despite a trend for a better OS than the historical data available (12-13 ms). This TNBC ESME cohort is one of the largest available and offers an updated assessment of the outcomes of this population.

4504Background: Until 2014, standard treatment for poor-prognosis GCT was 4 BEP plus surgery and cure was achieved in only 50% of patients (pts) (IGCCCG 1997). The tumor marker decline rate identif...

e20655 Background: Guidelines recommend granulocyte-colony stimulating factor use to reduce the risk of neutropenic complications in patients receiving CT and to enable delivery of full-dose CT. ZO...

4562 Background: The anterior mediastinum is the most common location for extra-gonadal germ-cell tumors. MGCT has poor prognosis (International Germ Cell Consensus Classification); overall surviva...

365 Background: GETUG 13 investigated personalized chemotherapy based on tumor marker decline in patients with poor-prognosis GCT and demonstrated that a dose-dense regimen improves progression-free survival in patients with an unfavorable decline (Fizazi K, ASCO 2013). We investigated the pattern of relapse for patients included in GETUG 13. Methods: We conducted an analysis of relapse events in patients from GETUG 13 and an unfavorable decline of tumor markers (n=203). Baseline procedures before inclusion in the trial comprised a thoraco-abdomino-pelvic CT scan and an MRI of the brain: 22 patients (10%) had evidence of brain metastases at presentation. Results: With a median follow-up of 4.1 years (0.3 ; 8.8 years) when the analysis was performed, a progression event was observed in 94/203 patients (46%). First event consisted in a marker progression only in 41 patients (43%), a radiographic progression only in 29 patients (31%), a mix progression on both markers and imaging in 11 patients (12%), and death in 13 patients (14%). In patients with radiographic progression only, brain was the predominant site (n=16/29, 55%). Among all patients who experienced a radiographic progression (as first and subsequent progression event, n=58), brain only was the site of progression in 26 patients (45%): 12/30 (40%) in patients treated with BEP and 14/28 (50%) in those treated with dose-dense chemotherapy. Conclusions: Brain metastases develop often, early, and frequently as the only site of relapse in the course of poor-prognosis GCT. This raises the question of early detection and treatment of brain metastases in these patients, for example by integrating a systematic brain MRI after 2-3 months of chemotherapy.

LBA4500 Background: Poor-prognosis GCT (IGCCCG, J Clin Oncol 1997) remains a challenge with no improvement in the 50% survival demonstrated in phase III trials for 25 years. Day 21 serum tumor marker decline rate identified a subgroup of patients (pts) with a better outcome (J Clin Oncol 2004, 22: 3868-76). The hypothesis we tested in this study is that treatment allocation based on early tumor marker decline will improve the progression-free survival (PFS). Methods: Pts with IGCCCG poor-prognosis GCT were treated with a first cycle of BEP. AFP and hCG were assessed at day 18–21: 1) Pts with a favorable decline continued BEP for a total of 4 courses (Fav-BEP); 2) Pts with an unfavorable decline were randomized to receive either BEP (Unfav-BEP) or a dose-dense regimen (Unfav-dose-dense), consisting of paclitaxel-BEP plus day-10 oxaliplatin x 2 cycles, followed by 2 cycles of cisplatin, ifosfamide, and continuous infusion bleomycin (depending on lung function) + G-CSF. The primary endpoint was PFS (hypothesis: 20% difference, type 1 error: 5%, power 80%, 196 randomized pts needed). Results: 263 pts were enrolled and 254 were evaluable at day 21 (6 early deaths, 3 withdrawals): 51 pts (20%) had favorable tumor marker decline and 203 had unfavorable decline (randomized: 105 Unfav-dose-dense arm, 98 Unfav-BEP). The prognostic value of early tumor marker decline (Fav-BEP vs Unfav-BEP) was confirmed: 70% vs 48% for 3-year PFS (p=0.01), and 84% vs 65% for overall survival (OS) (p=0.02). The 3-year PFS was 59% in the Unfav-dose-dense arm vs 48% in the Unfav-BEP arm (p=0.05; HR: 0.66 [0.44-1.00]). 3-year OS was 73% and 65%, respectively. More ≥ grade 2 neurotoxicity (21% vs 4%) and more hematotoxicity occurred in the dose-dense arm, with no excess febrile neutropenia (17% each arm) or toxic deaths (1 each arm). Salvage high-dose chemotherapy + stem-cell transplant were required in 6% in the Unfav-dose-dense arm and 16% in the Unfav-BEP arm (p=0.01). Conclusions: An algorithm of individualized treatment intensification determined by the rate of early tumor marker decline reduces the risk of progression or death in men with poor-prognosis GCT. Clinical trial information: NCT00104676.

e16021 Background: Prostate cancer is a major problem in the aging male population. Docetaxel, the first-line reference treatment in CRPC induces a prostate-specific antigen (PSA) response in 45% of patients and an objective tumor response in 12%. Preclinical studies suggested that curcuminoids inhibit tumor metastasis, invasion and angiogenesis and reverse drug resistance. We wanted to potentiate docetaxel by curcuminoïds in CRPC first line. Our previous phase I study showed the safety and the tolerability of CCM associated to docetaxel for advanced breast cancers. We have conducted in 2009-2010 a phase II study to assess the response of CRPC to this combination. Methods: Patients (n=30) with progressing CRPC and rising PSA were enrolled to receive the experimental treatment. Docetaxel was given in standard conditions (75mg/m², 1h i.v infusion every 3 weeks for 6 cycles + prednisolone) with CCM orally at the dose of 6gr/day (7 days by cycle: d-4 to d+2). The primary endpoint was response rate assessed by biological and paraclinical examinations. The secondary endpoints included safety, time to progression and compliance. Twenty nine patients were evaluable on PSA assessment and 15 on RECIST criteria. Results: 26 patients received the treatment totality and 4 withdrew prematurely. No patient withdrew for toxicity (2 deaths and 2 PSA progressions). A PSA response was observed in 17/29 patients (59%) (4 complete and 13 partial) observed rapidly (before the 3rd cycle) for 15 patients. The median time to subsequent PSA progression (TTP) was 5.8 months. Six patients (40%) had a partial objective response and 9 (60%) a stable disease. The median TTP on targets was 7.85 months (n=13/15). The regimen was well tolerated, with uncommon grade 3/4 toxicity; no adverse event was attributed to CCM. Of 169 cycles, 150 (89%) were completed with perfect compliance. Overall survival was 19 months (mean) and 24 months (median) with 17 events as of december 2012. Conclusions: These results are promising in improving the response rate to docetaxel in terms of both PSA decrease and objective response, with good tolerability and acceptability of CCM. A randomized trial is necessary to confirm this results. Clinical trial information: NCT01012141.

5075 Background: mPC pts experiencing a short period of sensitivity to initial androgen deprivation therapy (ADT) have an unfavourable prognosis and lower probability of response to 2nd-line endocrine therapy suggestive of androgen receptor (AR) pathway-independent mechanisms of resistance. Recent studies have shown that docetaxel may kill PC cells through AR targeting. We thus investigated whether docetaxel may have efficacy in pts with early CR. Methods: Two independent prospective databases (Institut Gustave Roussy and Institut Jean Godinot) of mCRPC pts were analyzed. Early CR was defined as progression within the first year of ADT. The primary endpoint was time to progression (TTP) on docetaxel. Secondary criteria were clinical benefit (decrease in 2 points on a 0-to-10-pain-scale or in dose or type of pain medication), PSA response (decrease > 50% in PSA serum level) and overall survival (OS). Pts with early CR were compared to pts with sensitivity to initial ADT > 1 year (t-test for quantitative data, χ-2 test or Fischer’s exact test for qualitative data, Logrank test for TTP and OS). Results: 188 pts were selected for analysis. A higher frequency of unfavourable prognostic factors in pts with early CR as compared with others pts was observed with a median PSA serum level of 81 ng/dl (4-8000) vs 35 ng/dl (4-4260) (p=5.10-5), presence of visceral metastasis in 11% vs 2% of pts (p=0.01) and Gleason score ≥ 8 in 63% vs 41% of pts respectively (p=0.001). Clinical benefit and PSA response on docetaxel were observed in 84% vs 89% of pts (p=0.45) and 67% vs 81% of pts (p=0.10) respectively. Median TTP was 6.1 months (95%CI=6-7.5) vs 7.8 months (95%CI=7-8.3) (p=0.04). Median OS was 22.4 months (95%CI=17.1–28.6) vs 36.1 months (95%CI=26.3–42.4) (p=0.002). Conclusions: mPC pts experiencing early CR have more unfavourable baseline prognostic factors, shorter TTP on docetaxel and shorter OS as compared with pts experiencing time to CR > 1 year. However, similar clinical and biological benefits from docetaxel chemotherapy were observed in this subset of pts. Since they have lower probability of response to second-line endocrine therapy, docetaxel appears as the best option after progression on initial ADT.

392 Background: In RECORD-1, the oral mTOR inhibitoreverolimus significantly improved PFS compared with placebo in patients with mRCC refractory to 1 or 2 prior VEGFr-TKIs. Here, we provide prospective data from European countries on everolimus use in patients with mRCC after failure of anti-VEGF therapy. Methods: To evaluate the safety and efficacy of everolimus in routine clinical practice, data were pooled from 4 prospective, noninterventional studies conducted in Germany, France, Greece, and Austria. Results: Data from the first 6 months of treatment are available for 534 patients. At baseline, median time since diagnosis of first metastasis from RCC was 1.8 years, and 91% of patients were of favorable or intermediate MSKCC risk prognosis. Predominantly clear cell mRCC was evident in 90% of patients, and most patients had prior nephrectomy (89%). Best overall response by investigator assessment was partial response in 13%, stable disease in 56%, and progressive disease in 32%. Overall, 77% of patients experienced ≥1 adverse event (AE) and 22% experienced ≥1 serious AE. AEs occurring in >5% of patients included stomatitis (25%), anemia (13%), asthenia (9%), fatigue (8%), pneumonitis (8%), rash (8%), diarrhea (7%), decreased appetite (7%), hypertriglyceridemia (6%), dyspnea (6%), nausea (6%), and peripheral edema (5%). Serious AEs occurring in >2% of patients included stomatitis (3.4%), general health deterioration (2.2%), anemia (2.1%), dyspnea (2.1%), and pneumonitis (2.1%). Median everolimus duration was 4.8 months. Treatment was discontinued due to disease progression in 50% of patients and AEs in 24% of patients. A similar proportion of patients had Karnofsky performance status ≥70 at baseline (86%) and at end of analysis (80%). Updated data will be available in February 2012. Conclusions: Preliminary results of this pooled analysis of 4 European studies substantiate the safety of everolimus reported in the pivotal RECORD-1 trial and provide evidence for the effectiveness of everolimus in routine use. The results support the use of everolimus as a standard of care for VEGF-refractory patients with mRCC.

211 Background: In the last 30 years, a major shift in initial staging has occurred for men with prostate cancer (CaP) in many Western countries, with the incidence of detectable metastases at diagnosis decreasing from more than half the cases in the 1970s to currently less than 10%. Still, prostate cancer is the second killing neoplasm in men. We used two prospective databases of patients with castration-resistant prostate cancer (CRPC) to describe the natural history of metastatic CRPC in the modern era. Methods: The outcome of 190 men with CaP treated for metastatic disease from 2007-2011 was studied. Characteristics of patients who died from CaP were analyzed. Results: After a median follow-up of 6.8 years, 112 patients had died from CaP and 109 were assessable for presence of metastasis at initial diagnosis. Of these 109 pts, 53 (49%) had detectable metastasis at diagnosis: 43 pts (81%), 6 pts (11%) and 17 pts (32%) had bone, visceral; and lymph nodes metastases, respectively. Overall, 10 pts (19%) had more than one metastatic site. Median time to CRPC was 16 months (range: 3-122 months) and median overall survival was 5 years (CI 95%: 4.6 – 6.6 years) for these pts with detectable metastasis at diagnosis. Among patients with localized CaP at diagnosis (n=56; 51%), 23 pts (41%) had T stage ≥ 3, 23 pts (41%) had a Gleason score ≥ 8. Their median PSA was 15 ng/ml (4-400). Overall, 39 pts (70%) were classified as having a high-risk CaP. 13 patients (23%) dying from CaP had an initial Gleason score ≤ 6. The median overall survival was 7 years (CI 95%: 6.1 – 9.1 years). Conclusions: In the modern era, approximately half of the patients eventually dying from CaP had detectable metastases at diagnosis. The paradigm of patients progressing from localized disease to metastatic disease and eventually death is represented only in the other half. Further efforts should be made to conduct clinical trials in patients with newly diagnosed metastatic prostate cancer.

e15142 Background: The TROPIC (Johann Sebastien de Bono et al ; Lancet 2010) study demonstrated that cabazitaxel (a novel tubulin-binding taxane drug) improves overall survival of patients (pts) with mCRPC who progressed during or after docetaxel-based chemotherapy, with a median survival of 15.1 months. Based on this result, a compassionate-use program has been established to provide pts with mCRPC the opportunity to receive the treatment, before licensing of the drug. Methods: ATU of cabazitaxel in France has been granted before its marketing authorization; all safety data from pts treated during this period were collected following a specific therapeutic use protocol. All participating physicians were instructed about the molecule by a company physician and contacted before the first treatment, on day 15 and at the end of treatment of each patient to make sure that all G3/4 and serious adverse events were collected. Results: We report baseline characteristics and safety data from the 184 pts treated in 92 French centers. Median age was 67.2 years (46 - 92), ECOG performance status was 0-1 for 85% of pts, 88% had bone metastases and 21% had visceral metastases. All the pts had received prior docetaxel, 55% had discontinued for disease progression; 85% of the pts received previously 1-2 lines of chemotherapy. Pts received a median of 3 cycles of cabazitaxel (1-6). Rates of grade 3-4 hematological toxicities were: neutropenia grade≥ 3 (4%), febrile neutropenia (3%), all resolved. All grade other toxicities were: nausea (0.5%), diarrhea (2.7%) and fatigue (0.5%). No treatment-related death was reported. Conclusions: The ATU program provides additional safety information on cabazitaxel in the real-life setting; they are consistent with the TROPIC study safety results. The incidence of neutropenia grade≥ 3 (4%) and febrile neutropenia (3%) appears to be lower than expected. Therapeutic use protocols such as these can be helpful for physicians when new therapies become available. Proactive education of healthcare givers on AEs management could be considered when new treatments are introduced.

e15069 Background: Prostate cancer is the most frequent tumor in men from developed countries. A previous phase I study showed the feasability of curcuminoids in association with docetaxel for adva...

1133 Background: Achieving pathologic complete response (pCR) is the main goal in NACT. PCR rates will be studied comparatively for stage II-IIIA operable breast cancer in 264 women, randomized to receive either 3 FEC 100 then 3 docetaxel 100 mg/m2 (standard arm A) or adapted arm B beginning with 2 FEC 100. Docetaxel will be given if tumor size decreased by less than 30 or 50 percent after 2 or 4 FEC 100, respectively; otherwise FEC100 was given for 6 courses before surgery. A new classification will assess the limited residual disease in breast and nodes (LRDBN) when obtained. Methods: 140 patients, all Her 2 negative with or without HR on microbiopsies, have been randomized to date with a median age of 52 years. They were repartited according to 2 tumour phenotypes : Her2-HR+ (luminal phenotype) and Her2-HR- (TN). 107 patients post NACT were operated. Pathological response was analyzed in 98 BC (77 Luminal; 18 TN) according to: Chevallier’s (Am J Clin oncol 1993), Sataloff’s (J Am Coll Surg 1995) and Re...

e15013 Background: Sunitinib is currently a standard of care for the treatment of mRCC. Hypothyroidism was frequently observed with sunitinib therapy. This study was conducted to determine the thyr...

620 Background: Pathological responses rates will be studied comparatively in 264 women with stage II-IIIA operable BC randomized to receive either 3 courses of FEC100 followed by 3 courses of taxo...

5003 Background: Satraplatin is a novel oral platinum compound previously reported to reduce risk of disease progression among HRPC pts progressing after prior CT. Herein the impact of satraplatin ...

5019 Background: Chemotherapeutic options for HRPC are limited. S is a novel oral platinum compound. Methods: The SPARC trial is a multinational randomized double blind study comparing S 80 mg/m2/day x 5 q5weeks po + prednisone (P) vs placebo + P in HRPC patients (pts) who failed prior chemotherapy. In this analysis, progression-free survival (PFS) was the primary endpoint, defined as a composite endpoint of radiologic progression, symptomatic progression, skeletal events or death. All cases were blindly adjudicated for progression by an independent review committee (IRC). Results: 950 pts were accrued between Sept 2004 and Jan 2006. Baseline characteristics were well balanced between treatment arms. 51% of the pts had received prior docetaxel. 68% were ≥ 65 yrs old and 27% were ≥ 75 yrs old. Pts received a median of 4 courses in the S arm (range:1–28) vs 2 courses in the placebo arm (range 1–16). 802 pts had an IRC defined progression-free (PFS) event consisting in 80% of the cases of radiologic progression, pain progression or death. All analyses were conducted on an intent-to-treat basis. S was associated with a 31% reduction in the risk of PFS events (HR=0.69; 95% CI: 0.60–0.80; p No significant financial relationships to disclose.

4561 Background: Estramustine phosphate is a mustard-estradiol conjugate, with evidence of both hormonal and non-hormonal effects. In phase II trials, the response rates of microtubule inhibitors are increased when combined with estramustine. Morbidity includes notably thrombosis in about 7% of cases. Whether combining estramustine with chemotherapy increases survival in castration-refractory prostate cancer (CRPC) is still controversial. Methods: Data from all published and unpublished prospective randomized trials assessing chemotherapy + estramustine versus chemotherapy alone in CRPC were sought using electronic database searching, hand searching, and by contacting experts in the field. The primary endpoint was overall survival (OS). The analysis was performed on an intention-to-treat basis. The stratified logrank test was used and an overall hazard ratio (HR) was computed using a fixed effect model. χ2 heterogeneity tests were used to test for statistical heterogeneity. All p-values were two-sided. Multivariate analysis was performed using a Cox model stratified by trial. Results: Individual data were obtained from all 5 randomized trials conducted in the PSA era that had been identified (n = 610). The control arms consisted of docetaxel (1), paclitaxel (1), ixabepilone (1), and vinblastine (2). With a median follow-up of 2.8 years, 510 deaths had occurred. OS was significantly better in the estramustine arm (HR = 0.82 [95% CI: 0.69–0.97]; p = 0.02). Overall, the risk reduction (RR) of death related to estramustine was 18% (± 8). There was no significant interaction (p = 0.66) between the RR of trials using vinblastine (RR = 15% [± 12]) and in those using taxanes or ixabepilone (RR = 21% [± 11]). The estimated 1-year OS rate was 57% and 50% in the estramustine arm and in the control arm, respectively. The 18-months OS rate was 43% and 35%, respectively. There was no interaction between the effect of estramustine and age, performance status, or serum PSA in the Cox model. Conclusions: Combining estramustine with chemotherapy increases OS over chemotherapy alone in patients with castration-refractory prostate cancer. [Table: see text]

4603 Background: Single-agent docetaxel has proven efficacy in pts with HRPC, but the D and E combination is synergistic in vitro. This study evaluated PSA decline (PSA↓), safety, and quality of life (QoL) for DE vs D. Methods: Major eligibility criteria were: WHO PS \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\underline{{

617 Background Although recent results have shown the effectiveness of taxanes in the adjuvant treatment of BC, its influence is still under evaluation in most countries. . Methods The primary aim of this randomised trial was to determine whether 4 cycles of adjuvant AT (adriamycin 50 mg/m2 docetaxel 75 mg/m2) will prolong disease-free survival when compared to 4 cycles of AC (adriamycin 60 mg/m2 cyclophosphamide 600 mg/m2) in women age 18–70 with resected high-risk pN0 (Saint Gallen Consensus) or limited pN+ (≤ 3) invasive BC. Chemotherapy was delivered q3w without prophylactic filgrastim, followed by tamoxifen 20 mg/day for 5 years in pts with ER±PgR-positive tumours and radiation therapy according to standard guidelines. The trial planned to recruit 700 pts over 36 months. Results Between 6/1999 and 1/2003, 627 pts were randomised. Pt and tumour characteristics were well balanced between treatment groups: median age 52.2 years; premenopausal 47.9%; clinical tumour size ≤ 2.0/2.1–5 cm 53.5/42.8%; breast...