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Background Abiraterone (Abi), enzalutamide (Enz) and docetaxel (Doc) are all approved first-line (1L) treatment options for mCRPC. However, the optimal treatment sequence has not been established yet. In the present analysis, we explored the outcomes of pts treated with 1L Doc or Abi/Enz in the prospective PROREPAIR-B cohort study (NCT03075735). Methods We assessed the impact of 1L treatment options (Doc vs Abi/Enz) on progression-free survival to 1L therapy (PFS) and overall survival (OS). Uni- (UV) and multivariable (MV) Cox-regression models were used. MV model covariates included age (≥75 years), local therapy, Gleason Score, visceral metastases, metastases at diagnosis, phosphatase alkaline (ALP) (≥ULN), lactate dehydrogenase (LDH) (≥ULN), haemoglobin (Hb) (≤LNL), albumin (≤LNL) and ECOG performance status. Results Of 419 pts enrolled in the study, 406 received 1L Doc (n = 188) or Abi/Enz (n = 218). Overall, pts receiving Doc were younger (p = 0.002), had higher rates of visceral metastases (17.6% vs 8.7%, p = 0.008), ALP (52.1% vs 40.4%, p = 0.018), LDH (48.1% vs 31.2%, p Conclusions Pts treated with 1L Doc had worse baseline prognostic features. Despite a longer PFS was observed in pts treated with 1L Abi/Enz vs Doc, no difference in OS was found between the treatment sequences. Similar results were observed in the elderly population. Biomarker-driven pts selection is needed to identify the optimal sequence. Clinical trial identification NCT03075735. Legal entity responsible for the study Centro Nacional de Investigaciones Oncologicas (CNIO). Funding Unrestricted grant from Fundacion Cris Contra el Cancer; three investigator awards from the Prostate Cancer Foundation (C.C.P. [2013], D.O. [2014], and E.C. [2017]); and three grants from Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III (No. PI13/01287 and PI16/01565 to D.O. and No. PI15/01471 to P.L.). During the conduct of this study, E.C., D.O., P.N., and L.M-P. were supported by grants from Ministerio de Economia, Industria y Competitividad (No. JCI-2014-19129 [E.C.], No. RYC-2015-18625 [D.O.], No. SVP-2013-067937 [P.N.], No. SVP-2014-068895 [L.M.]); D.O. was also funded by a Return fellowship from Fundacion Cientifica de la Asociacion Espanola Contra el Cancer, 2012-2015; N.R.L. and R.L., by grants from Instituto de Salud Carlos III (No. CM14-00200 to N.R.L. and No. CM17-00221 [R.L.]); and Y.C., by a grant from Ministerio de Educacion, Cultura y Deportes (No. FPU15/05126). C.C.P. was supported by a congressional-designated medical research program award (No. CMRP-PC131820). Disclosure C. Cattrini: Travel / Accommodation / Expenses: Novartis, Ipsen. N. Romero Laorden: Honoraria (self): MSD, Sanofi-Aventis, Astellas, Janssen-Cilag; Travel / Accommodation / Expenses: Bayer, Janssen-Cilag, Roche, PharmaMar; Research grant / Funding (institution): Bayer, Astellas, Janssen, Sanofi. E. Castro: Honoraria (self): Astellas Pharma, Janssen-Cilag, AstraZeneca, Bayer, Pfizer; Advisory / Consultancy: Bayer, Janssen-Cilag; Research grant / Funding (institution): Janssen-Cilag, AstraZeneca, Bayer; Travel / Accommodation / Expenses: Bayer, Janssen-Cilag, Roche, Astellas Pharma. I. Garcia-Carbonero: Advisory / Consultancy: Janssen Oncology, Astellas Pharma, Bayer, Sanofi; Travel / Accommodation / Expenses: Astellas Pharma, Janssen, Sanofi, Bayer. J.M. Piulats: Advisory / Consultancy: Janssen Oncology, Astellas Pharma, VCN Biosciences, Clovis Oncology, Roche, Genentech, Bristol-Myers Squibb, Merck Sharp & Dohme; Research grant / Funding (institution): Bristol-Myers Squibb, AstraZeneca, MedImmune, Merck Sharp & Dohme, Pfizer, EMD Serono, Incyte, Janssen Oncology; Travel / Accommodation / Expenses: Janssen Oncology, Roche, Bristol-Myers Squibb. J. Puente: Advisory / Consultancy: Pfizer, Astellas Pharma, Janssen-Cilag, Merck Sharp & Dohme, Bayer, Roche, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Ipsen, Eisai, EUSA Pharma, Sanofi; Speaker Bureau / Expert testimony: Pierre Fabre, Celgene, Kiowa, Novartis, Lilly; Research grant / Funding (institution): Astellas Pharma, Pfizer; Research grant / Funding (institution): Pfizer, Roche, Janssen-Cilag. B. P. Valderrama: Honoraria (self): Pierre Fabre, Astellas Pharma, Novartis, Bristol-Myers Squibb, Ipsen; Advisory / Consultancy: Astellas Pharma, Novartis, Pfizer, Pierre Fabre, Bayer, Sanofi, Bristol-Myers Squibb, Roche, Ipsen; Travel / Accommodation / Expenses: Janssen-Cilag, Bristol-Myers Squibb. E. Gonzalez Billalabeitia: Travel / Accommodation / Expenses: Bristol-Myers Squibb, Pfizer, Janssen-Cilag, Astellas Pharma, Sanofi. R. Morales Barrera: Honoraria (self): MSD, Sanofi, AstraZeneca, Asofarma, Johnson and Johnson, Roche/Genentech; Advisory / Consultancy: MSD, Sanofi, AstraZeneca, Asofarma, Johnson and Johnson, Roche/Genentech; Speaker Bureau / Expert testimony: MSD. Sanofi, AstraZeneca, Asofarma, Johnson and Johnson; Research grant / Funding (institution): AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, INC, Astellas Pharma., AstraZeneca AB, Aveo Pharmaceuticals INC, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim Espana, S.A., Bristol-Myers Squibb Intern; Travel / Accommodation / Expenses: MSD, Roche/Genentech, Lilly, Clovis Oncology, Bayer, Johnson and Johnson, Astellas Pharma, AstraZeneca. R. Lozano Mejorada: Honoraria (self): Roche, Janssen-Cilag, Bayer; Research grant / Funding (institution): Bayer, Janssen-Cilag; Travel / Accommodation / Expenses: Roche, Janssen-Cilag, Astellas Pharma. R. Luque: Honoraria (self), Travel / Accommodation / Expenses: Janssen-Cilag, Sanofi Aventis, Astellas Medivation, Roche, Novartis, Pfizer, Bristol-Myers Squibb, EUSA Pharma. E. Martinez Ortega: Honoraria (self), Travel / Accommodation / Expenses: Sanofi Aventis, Roche, Pfizer Bristol Mayers Squibb, EUSA Pharma and IPSEN. J.A. Arranz Arija: Honoraria (self): Novartis MSD Oncology Janssen-Cilag EUSA Pharma Astellas Pharma Bristol-Myers Squibb; Advisory / Consultancy: Pfizer Astellas Pharma Janssen-Cilag Novartis Bayer Ipsen MSD Oncology Bristol-Myers Squibb EUSA Pharma; Research grant / Funding (institution): Novartis Pierre Fabre Bristol-Myers Squibb; Travel / Accommodation / Expenses: Bristol-Myers Squibb Janssen-Cilag MSD Oncology Pfizer. E. Gallardo Diaz: Honoraria (self): Astellas Pharma, Roche, Bristol-Myers Squibb, Novartis; Advisory / Consultancy: Pfizer, Bayer Schering Pharma, Janssen Oncology, Astellas Pharma, Roche, Bristol-Myers Squibb, Sanofi, Ipsen, Eisai, Rovi, Daiichi Sankyo, EUSA Pharma; Speaker Bureau / Expert testimony: Rovi, LEO Pharma, Menarini, Bristol-Myers Squibb, Ipsen, Astellas Pharma, Roche, Daiichi Sankyo; Travel / Accommodation / Expenses: Pfizer, Astellas Pharma, Pierre Fabre, Bayer Schering Pharma, Bristol-Myers Squibb, Eisai, Janssen, Roche. E. Almagro Casado: Speaker Bureau / Expert testimony: MSD; Travel / Accommodation / Expenses: Bristol-Myers Squibb. M.J. Mendez Vidal: Advisory / Consultancy: Janssen-Cilag, Pfizer, Astellas Pharma, Sanofi, Bayer, Bristol-Myers Squibb, Novartis, Roche; Travel / Accommodation / Expenses: Janssen-Cilag, Pfizer, Astellas Pharma, Bristol-Myers Squibb. D. Olmos Hidalgo: Speaker Bureau / Expert testimony: Astellas, Bayer, Janssen, Sanofi; Advisory / Consultancy: Astellas, AstraZeneca, Bayer, Genentech, Janssen, Clovis; Research grant / Funding (institution): Astellas, AstraZeneca, Bayer, Genentech/Roche, Janssen (Incl.Aragon), Medivation/Pfizer, Tokai, MSD, GSK; Travel / Accommodation / Expenses: Bayer, Janssen-Cilag, Ipsen. D. Lorente: Honoraria (self): Janssen-Cilag, Bayer, Astellas Pharma, Sanofi; Advisory / Consultancy: Janssen-Cilag, Bayer, Sanofi; Travel / Accommodation / Expenses: Sanofi, Astellas, Janssen-Cilag, Celgene. All other authors have declared no conflicts of interest.

Background Due to improved outcome in mCRPC, most prognostic models may not reflect the current treatment landscape. Recently, Armstrong et al (Ann Oncol 2018) published a prognostic model based on the phase III PREVAIL trial. Methods We applied the Armstrong prognostic model to patients (pts) treated in the COU-AA-302 trial. Variables included in the model: albumin, ALP, Hb, LDH, NLR, number of bone metastases, pain, pattern of spread, PSA, time from diagnosis. Pts were categorized into low ( Results 918 pts (84,4%) had data on all variables. Risk score (continuous) was associated with OS (HR 2.19; p Table . 864P OS rPFS TTPSAP Low 41.7m (38.7-46.8) 16.4m (13.8-19.1) 11.1m (8.3-11.2) Intermediate 24.6m (23.1-26.8) 8.3m (8-11) 5.6m (5.5-8.2) High 16.7m (11.7-30.2) 3.9m (3.6-4.1) 5.3m (3.7-8.3) Conclusions The Armstrong model is valid for mCRPC pts treated with first-line abiraterone. Less pts with high-risk features were included in COU-AA-302 than PREVAIL. These results may improve individual prognostic estimation and patient stratification in clinical trials. Study carried out under YODA Project #2018-3813. Clinical trial identification NCT00887198. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure D. Lorente: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer. All other authors have declared no conflicts of interest.

Background Ra223 is a bone-seeking a-emitter targeted therapy that induces double-strand DNA breaks (DSBs). The HR pathway is used to accurately repair DSBs and a significant proportion of mCRPC patients harbor pathogenic germline HR mutations (gHR+). We hypothesize that gHR+ patients, with an impaired ability to repair DSBs, are more likely to respond to Ra223 than gHR- patients. Methods This is an exploratory preplanned analysis of the PRORADIUM study (NCT02925702). PRORADIUM is a prospective observational biomarkers study of mCRPC patients treated with standard-of-care Ra223. Participants were screened for germline mutation in DNA damage and response genes using a multigene panel (Castro et al. J Clin Oncol 2019). Alkaline Phosphatase (ALP) response at 12 weeks was the primary endpoint. PSA response at 12 weeks, overall survival (OS) from Ra223 and clinical and/or radiographic progression free survival (PFS) were also analyzed. Results 161 out of 168 patients enrolled in PRORADIUM with available germline testing results were included. A pathogenic gHR mutation was identified in 14 (8.7%) patients (5 BRCA2, 4ATM, 1 BRCA1, 1 BRCA1+CHEK2, 1 BRIP1, 1 NBN, 1 BLM). Median age was 74 years (range 46-90). Performance status ECOG 1 was recorded in 91% pts. Median number of prior therapy lines for mCRPC was 2 (range 1-4) including at least one taxane in 63% patients. 54% of patients received 5 or 6 cycles of Ra223. After a median follow-up of 20 months, a>30% decline in ALP at 12 weeks was observed in 75% of gHR+ patients compared to 43% of gHR- (p=0.036). No differences in PSA >50% decline at 12 weeks (14% vs 8%, p=0.437) or in PFS (4.5 vs 5.0 months, p=0.670) were observed by gHR status. A trend towards more prolonged OS from Ra223 was observed in gHR+(median 14.4 vs 10.6 months, p=0.066). Conclusions In our study, germline HR mutations were associated with improved ALP responses, suggesting a greater benefit from Ra223 in gHR+ patients. Clinical trial identification NCT02925702. Legal entity responsible for the study The authors. Funding Bayer. Disclosure E. Castro: Honoraria (self), Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Travel / Accommodation / Expenses: Roche; Honoraria (self): Pfizer. R. Lozano Mejorada: Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Janssen. M. Saez: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: EUSA pharma. U.F.F. De Giorgi: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy: Bristol-Myers-Squibb; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Janssen; Advisory / Consultancy: Merck; Advisory / Consultancy: Pfizer. N. Romero Laorden: Advisory / Consultancy: Bayer; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): Astellas; Honoraria (self): Sanofi; Honoraria (self), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self): PharmaMar. G.A. De Velasco Oria de Rueda: Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Ipsen; Honoraria (self): Astellas; Honoraria (self): Bristol-Myers-Squibb; Honoraria (self): Bayer; Honoraria (self): Roche. J. Puente: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Merck; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers-Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Clovis; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eisai; Advisory / Consultancy: EUSA Pharma; Advisory / Consultancy: Sanofi; Speaker Bureau / Expert testimony: Pierre Fabre; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Kiowa; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer. A. Gonzalez del Alba: Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy: Janssen; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Novartis; Advisory / Consultancy: Eusa Pharma; Advisory / Consultancy: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers-Squibb; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD. P. Borrega Garcia: Advisory / Consultancy: Janssen; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Bayer; Advisory / Consultancy: Sanofi. V. Conteduca: Honoraria (self), Travel / Accommodation / Expenses: Astellas; Honoraria (self), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy: Bayer. A. Rodriguez-Vida: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy: Bristol-Myers-Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Sanofi; Research grant / Funding (self): Takeda. A. Medina Colmenero: Honoraria (self), Advisory / Consultancy: Astellas Pharma; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self): Janssen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Novartis; Advisory / Consultancy: Sanofi. R. Morales Barrera: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Asofarma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Johnson and Johnson; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Clovis; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Astellas. D. Lorente: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Travel / Accommodation / Expenses: Celgene. D. Olmos Hidalgo: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Clovis; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Tokai; Research grant / Funding (institution): Pfizer. All other authors have declared no conflicts of interest.

Background Clinically meaningful measures of response are needed in mCRPC. Post-treatment CTC decline have shown to be superior to PSA response in determining outcome in pts treated with AR signalling inhibitors. We compared the performance of CTC and PSA measures of response in mCRPC Doc-treated pts. Methods Baseline and post-treatment (6 to 9 weeks) CTC of mCRPC pts treated with Doc at first or second-line in a prospective study were determined with CellSearchTM platform. CTC response was defined: 30% decline from baseline (CTC30%), conversion (≥5 to 0 baseline CTC (CTC0). PSA response was determined at 12w as 30% (PSA30) or 50% decline (PSA50) from baseline. Cox-regression model were used to evaluate the association of baseline CTC (BLCTC), CTC response and PSA response measures with overall survival (OS), progression-free survival (PFS) or time to PSA progression (TTPP). C-index were used to evaluate the performance of each of the Cox regression model. Results 80 pts had evaluable BLCTC, 52 had evaluable post-treatment CTC count. Of 80 eligible pts, 53 (66.3%) received Doc at first-line. Median OS was 19 m (95%CI:16.4-21.8); median BLCTC was 7. BLCTC were associated with bone mts, higher PSA, ALP and LDH, and lower albumin levels. BLCTC was associated with OS (HR: 3.5; p Table . 889P N (%) HR (95%CI); p-value C-index CTC Conv 27 (51.9) 0.33 (0.18-0.60); p 0.665 CTC0 8 (15.4) 0.26 (0.10-0.67); p = 0.005 0.602 CTC30% 34 (65.4) 0.33 (0.18-0.61); p 0.644 PSA30 32 (61.5) 0.72 (0.40-1.30); p = 0.271 0.563 PSA50 22 (42.3) 0.68 (0.38-1.20); p = 0.183 0.595 Conclusions Baseline CTC were associated with OS, PFS and TTPP. CTC response measures were significantly associated with outcome, and showed a greater performance than PSA response measures in mCRPC Doc-treated pts. Legal entity responsible for the study Spanish National Cancer Research Center (CNIO) and The Institute of Cancer Research (ICR). Funding Has not received any funding. Disclosure R. Lozano Mejorada: Honoraria (self): Roche, Janssen-Cilag, Bayer; Research grant / Funding (institution): Bayer, Janssen-Cilag; Travel / Accommodation / Expenses: Roche, Janssen-Cilag, Astellas Pharma. D. Lorente: Honoraria (self): Janssen-Cilag, Bayer, Astellas Pharma, Sanofi; Advisory / Consultancy: Janssen-Cilag, Bayer, Sanofi; Travel / Accommodation / Expenses: Sanofi, Astellas, Janssen-Cilag, Celgene. E. Castro: Honoraria (self): Astellas Pharma, Janssen-Cilag, AstraZeneca, Bayer, Pfizer; Advisory / Consultancy: Bayer, Janssen-Cilag, AstraZeneca, Clovis Oncology; Research grant / Funding (institution): Janssen-Cilag, AstraZeneca, Bayer; Travel / Accommodation / Expenses: Bayer, Janssen-Cilag, Roche, Astellas Pharma. N. Romero Laorden: Honoraria (self): MSD, Sanofi-Aventis, Astellas, Janssen-Cilag; Travel / Accommodation / Expenses: Bayer, Janssen-Cilag, Roche, PharmaMar; Research grant / Funding (institution): Bayer, Astellas, Janssen-Cilag, Sanofi-Aventis. E. Almagro Casado: Honoraria (self): MSD; Travel / Accommodation / Expenses: BMS. M. Saez: Honoraria (self): Bristol-Myers Squibb, Pfizer, Novartis, Bayer, Janssen-Cilag, Sanofi-Aventis, Astellas Pharma, Ipsen, EUSA Pharma; Advisory / Consultancy: Bristol-Myers Squibb, Pfizer, Novartis, Bayer, Janssen-Cilag, Sanofi-Aventis, Astellas Pharma, Ipsen, EUSA Pharma; Travel / Accommodation / Expenses: Bristol-Myers Squibb, Pfizer, Novartis, Bayer, Janssen-Cilag, Sanofi-Aventis, Astellas Pharma, Ipsen, EUSA Pharma. D. Olmos Hidalgo: Honoraria (self): Janssen-Cilag, Bayer, Sanofi; Advisory / Consultancy: Bayer, Janssen-Cilag, AstraZeneca, Clovis Oncology; Research grant / Funding (institution): Bayer, Janssen-Cilag, AstraZeneca, Roche/Genentech, Medications/Pfizer, Astellas, Tokai, MSD, GSK; Travel / Accommodation / Expenses: Bayer, Janssen-Cilag, Ipsen. All other authors have declared no conflicts of interest.

Background Different therapeutic options have been approved in the last decade for the management of mCRPC. New prognosis biomarkers are necessary in the clinical practice to determine the optimal treatment sequence. In recent years, a number of studies have suggested an association between SNPs in androgen related-genes and outcome. Methods Abi or Enza-treated mCRPC patients (pts) in the PROREPAIR-B study (NCT03075735) were included. Nine SNPs within the six candidate genes, namely, CYP17A1 (rs2486758), SCLO2B1 (rs1077858), SRD5A1 (rs3736316 and rs3822430), SRD5A2 (rs2300700), HSD3B1 (rs1047303) and SULT1E1 (rs10019305, rs4149534 and rs3775777) were genotyped. Genotyping was performed using predesigned and custom Taqman SNP genotyping assays (Applied Biosystems, Foster City, CA) and 7500 Fast Real-Time PCR systems (Applied Biosystems, Foster City, CA). The allele calls were identified by specific software. Associations between genotypes and overall survival (OS), time to PSA progression (TTPP) and time to castration resistance (TCR) were calculated with bivariate Cox-regression models including line of treatment. Kaplan Meier estimates of survival were calculated. Results 322 pts treated with Abi (n = 259; 80.4%) or Enza (n = 63; 19.6%) were included in the analysis. Pts received Abi/Enza as first (n = 209; 64.9%), second (n = 111; 34.5%) or third (n = 2; 0.6%) line. Median OS was 25.9 m (95% CI: 23.5-28.3); median TTPP was 7 m (95% CI: 6.1-7.9) and median TCR was 29.1 m (95% CI: 24.1-34.1). rs3822430 SRD5A1 (0.82 [95% CI: 0.72-0.95]; p = 0.007) an rs3736316 SRD5A1 (HR: 0.86 [0.74-0.99]; p = 0.033) showed a significant association with OS. rs2486758 CYP17A1 (HR: 0.78 [0.64-0.95]; p = 0.014) showed a significant association with TCR. No SNPs showed an association with TTPP. Conclusions In our series (PROREPAIR-B) not significant associations were observed between most of the evaluated SNPs and outcomes in mCRPC patients treated with Abi or Enza. Legal entity responsible for the study Centro Nacional de Investigaciones Oncologicas (CNIO). Funding Has not received any funding. Disclosure D. Lorente: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen-Cilag; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas Pharma; Travel / Accommodation / Expenses: Celgene. R. Lozano Mejorada: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen-Cilag; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Astellas-Pharma. N. Romero Laorden: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas-Pharma; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen-Cilag; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi-Aventis; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: PharmaMar; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche. A. Medina Colmenero: Honoraria (self), Travel / Accommodation / Expenses: Janssen-Cilag; Honoraria (self): Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Janssen-Cilag; Travel / Accommodation / Expenses: Sanofi; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Novartis. J. Puente: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen-Cilag; Advisory / Consultancy: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Pierre Fabre; Speaker Bureau / Expert testimony: Celgene; Advisory / Consultancy: Kiowa; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Eisai; Advisory / Consultancy: Eusa Pharma; Advisory / Consultancy: Boehringer Ingelheim. R. Villatoro: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas-Pharma; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol. S. Vazquez Estevez: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim. J.M. Piulats: Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen Oncology; Advisory / Consultancy: Astella Pharma; Advisory / Consultancy: VCN Biosciences; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Clovis Oncology; Research grant / Funding (self): Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Research grant / Funding (self): Incyte; Research grant / Funding (self): MedImmune; Research grant / Funding (self): EMD Serono; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb. N. Lainez: Advisory / Consultancy: Astellas-Pharma; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer. A. Gonzalez del Alba: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Astellas-Pharma; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen Oncology; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: MSD Oncology; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: EUSA Pharma; Advisory / Consultancy: Ipsen; Full / Part-time employment: SERMAS. D. Olmos Hidalgo: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self): Sanofi; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Clovis Oncology; Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Tokai Pharmaceuticals. E. Castro: Honoraria (self), Travel / Accommodation / Expenses: Astellas-Pharma; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Roche; Honoraria (self), Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.

Background Ra223 is a life-prolonging alpha-emitter bone targeted therapy for mCRPC patients with bone metastases. However, evidence on biomarkers that may help us in patient selection are lacking. Total ALP (tALP) appeared to be a potential marker of Ra223 effect in early studies (Sartor, Ann Oncol, 2017). Other bone-related markers, as bone-specific ALP (BALP), have demonstrated its prognostic value in mCRPC patients with bone metastases (Fizazi K, Eur Urol, 2015; Lara PN, J Natl Cancer Inst, 2014). Methods PRORADIUM (NCT022925702) is a prospective multicentre cohort study in mCRPC patients treated with Ra223. The primary aim was to assess the impact of baseline serum biomarkers of bone formation (BALP and C-terminal of type 1 collagen propeptide [CICP]) on overall survival (OS). Secondary aims include the correlation of progression-free survival (PFS), time to PSA progression (TTPP) and skeletal-related events free-survival (SRE-FS) with serum bone markers. Results 142 out of 168 pts enrolled in the study were included in this preliminary analysis. Median age was 74 yrs, 85.5% pts had ECOG 0-1, 52% pts completed 5-6 cycles of Ra223. Higher baseline levels of BALP and CICP were associated to number of metastases in bone-scan (p = 0.007 and p = 0.016, respectively) and baseline pain (p = 0.014 and p = 0.050, respectively). After a median follow-up of 18 months, 91 deaths were observed, with a median OS of 11.5 months (95%CI: 9.1-13.9). Patients with baseline BALP and CICP values above the median showed a trend to shorter TTPP (BALP: 2.8 vs 3.1 m, p = 0.016; CICP: 2.8 vs 3.0 m, p = 0.091) and PFS (BALP: 4.4 vs 5.1 m, p = 0.070; CICP: 4.2 vs 5.5 m, p = 0.281), respectively. The elevation of bone markers above the median was significantly associated with worse OS (BALP: 8.8 vs 17.9 m, p Conclusions Our results suggest that baseline serum markers of bone formation may serve as biomarkers for prognosis in mCRPC patients treated with Ra233. Clinical trial identification NCT022925702. Legal entity responsible for the study IBIMA and CNIO. Funding Bayer, CRIS Cancer Foundation, Grant from Instituto de Salud Carlos III (PI16/01565). Disclosure N. Romero Laorden: Honoraria (self), Travel / Accommodation / Expenses: Bayer, Astellas Pharma, Janssen-Cilag, Sanofi-Aventis, PharmaMar, MSD, Roche. R. Lozano Mejorada: Honoraria (self): Roche, Janssen-Cilag, Bayer; Research grant / Funding (institution): Bayer, Janssen-Cilag; Travel / Accommodation / Expenses: Roche, Janssen-Cilag, Astellas Pharma. E. Almagro Casado: Honoraria (self): MSD; Travel / Accommodation / Expenses: BMS. E. Gonzalez Billalabeitia: Travel / Accommodation / Expenses: BMS, Pfizer, Janssen-Cilag, Astellas Pharma, Sanofi. A. Montesa: Advisory / Consultancy: Janssen-Cilag, Pfizer, Sanofi, Astellas Pharma; Travel / Accommodation / Expenses: Pfizer. G.A. De Velasco Oria de Rueda: Honoraria (self), Advisory / Consultancy: Pfizer, Novartis, Ipsen, Astellas Pharma, BMS, Bayer, MSD, Roche. R. Morales Barrera: Honoraria (self): MSD, Sanofi, AstraZeneca, Janssen, Roche/Genentech; Advisory / Consultancy: MSD, Sanofi, AstraZeneca, Janssen, Roche/Genentech; Speaker Bureau / Expert testimony: MSD, Sanofi, AstraZeneca, Asofarma, Janssen; Research grant / Funding (institution): AB Science, Aragon Pharmaceuticals, INC, Astellas Pharma, AstraZeneca, Aveo Pharmaceuticals, Bayer, Blueprint Medicines Corporation, BN Immunotherapeutics, Boehringer Ingelheim Espana, BMS, Clovis Oncology, Cougar Technology, Deciphera Pharmaceuticals LL; Travel / Accommodation / Expenses: MSD, Roche, Lilly, Clovis Oncology, Bayer, Janssen-Cilag, Astellas Pharma, AstraZeneca. D. Lorente: Honoraria (self): Janssen-Cilag, Bayer, Astellas Pharma, Sanofi; Advisory / Consultancy: Janssen-Cilag, Bayer, Sanofi; Travel / Accommodation / Expenses: Sanofi, Astellas, Janssen-Cilag, Celgene. E. Castro: Honoraria (self): Astellas Pharma, Janssen-Cilag, AstraZeneca, Bayer, Pfizer; Advisory / Consultancy: Bayer, Janssen-Cilag; Research grant / Funding (institution): Janssen-Cilag, AstraZeneca, Bayer, Genentech, Roche, Pfizer, Astellas Medivation, Tokai Pharmaceuticals; Travel / Accommodation / Expenses: Bayer, Janssen-Cilag, Roche, Astellas Pharma. D. Olmos Hidalgo: Honoraria (self): Janssen-Cilag, Bayer, Sanofi; Advisory / Consultancy: Bayer, Janssen-Cilag, AstraZeneca, Clovis Oncology; Research grant / Funding (institution): Bayer, Janssen, AstraZeneca, Roche/Genentech, Medivation/Pfizer, Astellas, Tokai, MSD, GSK; Travel / Accommodation / Expenses: Bayer, Janssen-Cilag, Ipsen. All other authors have declared no conflicts of interest.

Aim: The circulating tumor cells present morphological and genetic alterations. Our study is based on the association between the presence of KRAS mutations in circulating free cell DNA (ccfDNA) and the determination of genetically abnormal circulating cells (GACC), selecting these by size and the genetic alterations detected by FISH in patients who have undergone various treatments with metastatic colorectal cancer (CRCm). Methods: CTCs were quantified by means an automated fluorescence method (MetaFer-MetaCyte of MetaSystem), allowing selection of cells by size and genetic alterations. We analyzed mutation in plasma from KRAS gene by Pyrosequencing. Finally, we studied the association between KRAS mutation detected and the presence of 19 KRAS mutations in codons 12, 13, and 61 in FFPET CRC specimens. Results: Only 31 cells >7 micra were found in the controls out of the 36400 cells analyzed (0,08%). In the case of the patients, 389 cells were found (1.15%), the difference becoming statistically relevant after the MWW-test (p=0.001). None of the controls presented cells with two or more genetic alterations and over 7 micra in size, whereas 50% of the patients presented these characteristics despite having received treatment. 6 patients had a detectable plasma KRAS mutation in ccfDNA not previously found in the tumor. We found a connection between the presence of KRAS mutations in ccfDNA and the presence of GACC (p=0,048) Concordance between tumor-tissue analysis, ccfDNA analysys and GACC. Concordance between tumor-tissue analysis, ccfDNA analysys and GACC Tumor-tissue analysis GACC KRAS Mutant WT Yes No ccfDNA Mutant 11 6 13 4 WT 3 6 3 6 Total 14 12 Conclusions: In our study we found KRAS mutations in ccfDNA of multitreated metastatic colorectal cancer patients which is related to the presence of morphogenetically altered cells. Disclosure: All authors have declared no conflicts of interest.

Aim: Currently, several methods are available to detect CTCs in peripheral blood; the enumeration of CTCs has emerged as a promising biomarker. CTCs shed from metastatic cancers may allow the non-invasive analysis of the evolution of tumor genomes during treatment and disease progression through “liquid biopsies” 1. PIK3CA mutations and loss of PTEN expression are being analyzed in many studies in breast cancer. Frequent deregulation and aberration of this pathway have been implicated not only in breast cancer development and progression, but also in breast cancer therapy resistance, and as a potential predictor of response to new treatments 2,3. The objective of this study is to analyze genomic alterations of the PTEN gene and PIK3CA (exon 20) in CTCs in patients with MBC. 1. Cristofanilli M, et al. N Engl J Med 2004;351:781-91. 2. Sarah-Jane Dawson, et al. N Engl J Med 2013;368:1199-1209. 3. Cancer Genome Atlas Network. Nature 2012;490:61-70. Methods: We carried out a descriptive study in patients with MBC currently undergoing treatment at Hospital Universitario de Salamanca (Spain). CTCs were quantified by means an automated fluorescence method (MetaFer-MetaCyte of MetaSystem), allowing selection of cells by size and genetic alterations. We analyzed genomic alterations in PTEN gene in CTCs by FISH and High Resolution Melting (HRM) was performed to measure PIK3CA mutations in circulating tumor DNA. Finally, we studied the association between PTEN deletion and PIK3CA mutations. Results: In this preliminary analysis, a total of 30 samples have been obtained. CTCs (size >7 µm) were detected in 27 of 30 women. Of 27 samples, there were 12 cases (44,4%) of PTEN loss detected by FISH, and there were 10 cases (37,1%) in which PIK3CA mutations were detected by HRM. In 5 samples, there were association between PTEN deletion and PIK3CA mutations. These 5 cases were Luminal (A and B) tumors. Conclusions: Monitoring and isolation of CTCs represents an opportunity to study specific genomic alterations. In this study, we carried out the analysis of two genes involved in the same signaling pathway: PTEN and PIK3CA; which may have additive or synergistic effects through non-canonical functional pathways. Disclosure: All authors have declared no conflicts of interest.

Aim: The classification systems for febrile neutropenia F.N define groups of patients with high or low risk of developing complications during the episode, but they do not evaluate correctly which patients can be treated as outpatients, because up to 5-15 % of low risk patients suffer some kind of complication or even death. Methods: A retrospective study in only one institution of episodes of febrile neutropenia in outpatients with solid tumors between January 2004 and December 2011.The clinical differences between patients treated in hospital and those treated as outpatients were analyzed by means of a multivariate analysis to design a protocol algorithm. Results: A total of 250 patients were included. 173 (69.2%) patients underwent hospital treatment (PHT) and 77 (30.8%) were treated orally as outpatients (OP). Of the latter, none developed serious complications nor required admission. 12 clinical variables between PHT and OP were analyzed using logistic binary regression. Statistically significant differences were found, clinical factors favourable to outpatient treatment being: age 100/mm3 (OR, 14; 95% IC, 4,67 to 41,09); ECOG 10 days between cycle of chemotherapy (CC) and F.N episode (OR, 2,49; 95% IC, 1,01 to 6,19). The area under the curve for this model was 0.932 (p Conclusions: Ambulatory management is possible for patients with febrile neutropenia who are clinically stable and who present the above favourable clinical factors. Disclosure: All authors have declared no conflicts of interest.