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353 Background: Pre-clinical and retrospective clinical data support an interaction of metformin (MET) and radiotherapy. Thus, MET may represent a cost-effective means to improve radiotherapy outcomes. We sought to investigate whether MET increases time to progression (TTP) when combined with salvage radiation therapy (SRT) in men with recurrent prostate cancer after radical prostatectomy (RP). Methods: Non-diabetic men with biochemical recurrence after RP were enrolled into an open label, randomized, phase 2 study in 17 hospitals in Switzerland, France, and Germany. The randomization (1:1) was stratified by Gleason score ( 0.5 vs ≤ 0.5 ng/mL), ADT use, and evidence of local recurrence. Following randomization, patients received either prostate bed SRT (70Gy) or prostate bed SRT (70Gy) + MET. MET 850mg PO QD was given for 4 weeks before SRT, then 850mg PO QD for 48 weeks. The primary endpoint was TTP. Secondary endpoints were progression-free survival, undetectable PSA under normal testosterone levels, 50% PSA response, clinical progression-free survival, time to further systemic therapy, prostate cancer-specific survival, overall survival, and adverse events (AE). The trial design was powered for a HR 0.65 with planned enrollment of 170 patients. The trial was prematurely closed by the sponsor due to financial reasons. Data is reported after patients reached a minimum follow-up of 12 months after SRT and corresponds to the final analysis. Results: A total of 111 patients were randomized (106 evaluable) between 10/2017 and 11/2020. The median PSA at randomization was 0.3 ng/mL (range, 0.03-1.5 ng/mL), 19 patients (17.9%) had Gleason ≥8, 54 (50.9%) pT3 disease, and 50 (47.2%) positive surgical margins. Twenty-four patients (22.6%) used short-term ADT. Trial arms were well balanced. At a median follow-up of 27.1 months (95% CI: 26.7-27.8), a total of 16 progression events occurred. The median TTP was not reached in either treatment arm. The hazard ratio adjusted by stratification factors was 1.25 (95% CI: 0.40-3.94; one-sided 80% CI: 2.05; log-rank p=0.62). Two-year TTP was 89% (95% CI: 76%-96%) in the SRT arm vs 82% (95% CI: 67%-91%) in the SRT + MET arm. No statistically significant differences were found for the secondary endpoints. Most common AE during treatment was grade 1-2 diarrhea (24.1% SRT vs 54.6% SRT + MET). Grade 2 and 3 AE (gastrointestinal and/or urinary) were 25.9% and 3.7% with SRT vs 34.5% and 7.3% with SRT + MET (p=0.41 and p=0.68), respectively. Conclusions: Adding MET to SRT did not result in a significant improvement in TTP in non-diabetic men with recurrent prostate cancer post-RP. Because of early trial closure and fewer than expected events, the trial may have been underpowered for this endpoint. Additional correlative studies will be pursued. Clinical trial information: NCT02945813 .

383 Background: The clinical role of germline testing (GT) for prostate cancer (PC) is rapidly increasing due to the growing implications of precision medicine in metastatic disease, where genetic results can address eligibility for novel targeted treatments. Thus, ESMO and NCCN guidelines recommend GT for all metastatic PC individuals, whereas American testing criteria are more broad and include family history and other tumor features, such as high-risk disease, or intraductal or cribriform histology. Methods: We have retrospectively collected and analyzed clinical and genetic features of men with PC who underwent single-gene or multi-gene GT at some Swiss Institutions with expertise in hereditary cancers from July 2018 until October 2022. All patients (pts) have given written informed consent for research. Results: 109 men with PC underwent GT and received pre- and post-test counseling. Of these, 54 (50%) were metastatic, 34 (31%) had high-risk localized disease according to NCCN criteria, 7 (6%) presented cribriform or intraductal histology. A significant family history, as defined by current NCCN guidelines, was found in 79 (72%). 67 (61%) had no pathogenic (P) or likely pathogenic (LP) variants; 25 (23%) had a variant of unknown significance (VUS); 17 (16%) were found to have a P/LP variant in the following genes: BRCA2 (8), ATM (4), BRIP1 (1), FANCA (1), NBN (1), POT1 (1), TP53 (1). Among these 17 pts, the median age at diagnosis was 66 (45-80), 10 had metastatic disease, 5 had high-risk localized disease, 14 had a family history and 5 had a personal history of another cancer. Only 6 pts were

PURPOSE Pembrolizumab has previously shown antitumor activity against programmed death ligand 1 (PD-L1)–positive metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed the antitumor activity and safety of pembrolizumab in three parallel cohorts of a larger mCRPC population. METHODS The phase II KEYNOTE-199 study included three cohorts of patients with mCRPC treated with docetaxel and one or more targeted endocrine therapies. Cohorts 1 and 2 enrolled patients with RECIST-measurable PD-L1–positive and PD-L1–negative disease, respectively. Cohort 3 enrolled patients with bone-predominant disease, regardless of PD-L1 expression. All patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. The primary end point was objective response rate per RECIST v1.1 assessed by central review in cohorts 1 and 2. Secondary end points included disease control rate, duration of response, overall survival (OS), and safety. RESULTS Two hundred fifty-eight patients were enrolled: 133 in cohort 1, 66 in cohort 2, and 59 in cohort 3. Objective response rate was 5% (95% CI, 2% to 11%) in cohort 1 and 3% (95% CI, < 1% to 11%) in cohort 2. Median duration of response was not reached (range, 1.9 to ≥ 21.8 months) and 10.6 months (range, 4.4 to 16.8 months), respectively. Disease control rate was 10% in cohort 1, 9% in cohort 2, and 22% in cohort 3. Median OS was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3. Treatment-related adverse events occurred in 60% of patients, were of grade 3 to 5 severity in 15%, and led to discontinuation of treatment in 5%. CONCLUSION Pembrolizumab monotherapy shows antitumor activity with an acceptable safety profile in a subset of patients with RECIST-measurable and bone-predominant mCRPC previously treated with docetaxel and targeted endocrine therapy. Observed responses seem to be durable, and OS estimates are encouraging.

5042 Background: KEYNOTE-199 (NCT02787005) is a multicohort phase 2 study to evaluate pembrolizumab (pembro) in mCRPC. A previous analysis of patients with RECIST-measurable (cohort 4 [C4]) or bone-predominant nonmeasurable (cohort 5 [C5]) disease who were chemotherapy-naive and had progression while on enzalutamide (enza) found that pembro + enza showed antitumor activity and manageable safety. Long-term outcomes are of interest with immunotherapy; hence, updated efficacy and safety data after an additional 1 year of follow-up are presented. Methods: Pts were eligible if they had resistance to enza after prior response. Prior treatment with abiraterone was allowed. Pts received pembro 200 mg Q3W for up to 35 cycles + enza QD until progression, unacceptable toxicity, or withdrawal. Primary end point was ORR per RECIST v1.1 by blinded independent central review (BICR) in C4. Secondary end points were DOR (C4), and DCR, rPFS, OS and safety (both cohorts). Results: 126 pts (C4, 81; C5, 45) were treated. Median age was 72 years (range 43-92), 32.5% had visceral disease and 87.3% previously received ≥6 mo of enzalutamide; 121 pts (96.0%) discontinued, most because of progressive disease. Median (range) time from enrollment to data cutoff was 31.7 mo (23.1-37.1) in C4 and 35.5 mo (22.9-37.3) in C5. In C4, confirmed ORR was 12.3% (95% CI 6.1-21.5) (2 CRs, 8 PRs); median (range) DOR was 8.1 mo (2.5+ to 15.2), and 62.5% had a response ≥6 mo (Kaplan-Meier estimate). Additional efficacy analyses are outlined in the table. A total of 27.2% and 28.9% of pts in C4 and C5, respectively, experienced grade ≥3 treatment-related adverse events. Two pts in C4 died of immune-related AEs (Miller Fisher syndrome and myasthenia gravis). Incidence of any-grade (34.1%) and grade 3 or 4 (5.6%) rash, regardless of relatedness to treatment, was higher than previously reported for individual agents but manageable with standard-of-care treatments; 2 pts discontinued because of rash. Conclusions: After an additional 1 year of follow-up, pembro + enza continued to show antitumor activity and a manageable safety profile in pts with mCRPC who became resistant to enza. The treatment combination is being further evaluated in the ongoing phase 3 KEYNOTE-641 trial (NCT03834493). Clinical trial information: NCT02787005. [Table: see text]

5543 Background: Initial evidence suggests activity of pembro + enza in patients (pts) resistant to enza. We present results from the multicohort phase II study KEYNOTE-199 (NCT02787005) in chemotherapy-naive pts with mCRPC treated with pembro + enza after progression with enza and who had RECIST-measurable (C4) or bone-predominant (C5) disease. Methods: Pts who did or did previously receive abiraterone and for whom enza treatment failed after clinically meaningful response received pembro 200 mg Q3W, with continuation of enza for up to 2 y or until progression, toxicity, or withdrawal. End point was ORR per RECIST v1.1 (C4) by blinded independent central review (primary); DOR (C4), time to PSA progression, rPFS, OS, and safety. Results: A total of126 pts (C4, 81; C5, 45) were treated. Median (range) PSA was 31 ng/mL (0.4-1667) in C4 and 19 ng/mL (1-1750) in C5.Median (range) time from enrollment to data cut off was 15 mo (7-21) in C4 and 19 mo (7-21) in C5. In C4, ORR (95% CI) was 12% (6-22; 2 CRs, 8 PRs) and median (range) DOR was 6 mo (3+ to 13); 60% of pts had DOR ≥6 mo. DCR (CR + PR + SD) was 51% in C4 and C5. Median (95% CI) time to PSA progression was 4 mo (4-4) in C4 and 4 mo (4-4) in C5. Median (95% CI) rPFS was 4 mo (3-6) for C4 and 4 mo (3-6) for C5; 12-mo rPFS rate was 17% in C4 and 23% in C5. Median (95% CI) OS was NR (16-NR) in C4 and 19 (14-NR) mo in C5; 12-mo OS rate was 70% in C4 and 75% in C5. Shorter median OS was more associated with prior enza treatment

15 Background: KEYNOTE-199 (NCT02787005) is a multicohort phase 2 study. Cohort (C)4 (RECIST-measurable disease) and C5 (bone-predominant disease) consist of chemotherapy-naive patients (pts) with mCRPC treated with enza + pembro after progression with enza. Results for C4 and C5 presented. Methods: Pts with or without prior abiraterone had clinically meaningful response/benefit to enza followed by disease progression. Pts received pembro 200 mg Q3W with continuation of enza for up to 35 cycles or until progression/intolerable toxicity. Primary end point: ORR, blinded independent central review (C4). Secondary end points: DCR, PSA response rate (≥50% reduction), rPFS, OS, and safety (C4, C5); DOR (C4). Results: Of 126 pts (C4, 81; C5, 45), 107 discontinued, primarily due to progression. Median follow-up: 13.7 mo (C4, 11.8; C5, 18.6). ORR (95% CI) for pts with measurable disease was 12% (6-22) in C4; DCR for all pts: 51% (39-62) in C4 and 51% (36-66) in C5 (Table). Any grade/grade 3-5 treatment-related AEs occurred in 75%/26% pts in C4 and 69%/24% in C5. Two pts in C4 died of immune-related AEs (Miller Fisher syndrome and myasthenia gravis). Incidence of any grade/grade 3-4 rash (regardless of treatment relatedness) was higher than previously reported for individual agents (33%/6%). All except one pt (grade 3 treated with IV steroids) were treated with oral/topical steroids or had no intervention. Conclusions: Addition of pembro to enza following enza resistance showed modest antitumor activity in pts with RECIST-measurable and bone-predominant mCRPC. Combination had manageable safety and is being evaluated in a phase 3 trial. Clinical trial information: NCT02787005. [Table: see text]

Signaling networks play key homeostatic processes in living organisms but are commonly hijacked in oncogenesis. Prominent examples include genetically altered receptor tyrosine kinases and dysregulated intracellular signaling molecules. The discovery and development of targeted therapies against such oncogenic proteins has imparted clinical benefit. Nevertheless, concerns remain about the limited single-agent efficacy and narrow therapeutic indices of many of these antitumor agents. Moreover, it is apparent that oncogenic proteins comprise complex signaling networks that interact through crosstalk and feedback loops, which modify therapeutic vulnerability. These complexities mandate the study of drug combinations, which will also become necessary to reverse tumor drug resistance. Here, we outline the challenges associated with rational drug codevelopment strategies, with a focus on the importance of analytically validated biomarkers for patient selection and pharmacokinetic-pharmacodynamic (PK-PD) studies. Overall, the most informative clinical studies of novel combinations will have the following characteristics: robust scientific hypotheses leading to their selection; supportive preclinical data from contextually appropriate preclinical model systems; sufficient preclinical PK data to inform on the risk of drug-drug interactions; and detailed PD studies to determine the biologically active dose range for each agent. Toward this end, several novel clinical trial designs may be envisioned to accelerate successful drug combination development while minimizing the risk of late drug combination attrition. Although considerable challenges remain, these efforts may enable important steps to be taken toward more durable therapeutic control of many cancers.

2520Background: The VEGF/VEGFR and HGF/c-MET pathways are key mediators of the growth of solid tumours. MP0250 is a first-in-class, tri-specific DARPin compound neutralizing VEGF-A and HGF as well ...

5063Background: Declines in prostate specific antigen (PSA) levels at 12-weeks are currently used to evaluate treatments response in metastatic castration resistant prostate cancer (mCRPC). Early P...

TPS157 Background: Salvage radiotherapy (SRT) is as a potentially curative treatment for prostate cancer (CaP) patients presenting biochemical relapse after radical prostatectomy (RP). Metformin is a well-known antidiabetic drug that has demonstrated anti-cancer and radio-sensitizing effects. We aim to study whether metformin combined with SRT will improve cancer control by prolonging time to progression (TTP). Methods: This is a multicenter, randomized (1:1) phase II trial of SRT (70Gy/35fr to the prostate bed) with or without metformin (850mg BID for 52 wks) (NCT02945813). Metformin 850mg q.d. is started 4 wks prior to SRT. Stratification variables include Gleason score, PSA at randomization, surgical margin status and ADT use (allowed if PSA > 0.5, R0, post-RP PSA-DT < 6 mos or pT3b). Major eligibility criteria include: histologically proven CaP adenocarcinoma pT2a-3b, pN0 or cN0, M0; RP > 12 wks before registration; PSA progression after RP defined as 2 consecutive rises with final PSA > 0.1 ng/mL or 3 consecutive rises; and PSA ≤ 2 ng/mL within 14 days prior to registration. A sample size of 170 patients (85 per arm) is planned based on the primary endpoint TTP. Using a type I error of 5% and a power of 80%, 62 events are needed to show superiority of the treatment arm under the alternative hypothesis that the hazard ratio (HR) is 0.65 (TTP at 18 mos of 80% in the control arm vs. 86.5% in the treatment arm). All efficacy endpoints will be analyzed based on the full analysis population. The treatment effect will be assessed using Cox regression with the treatment arm as independent variable and the stratification factors as strata. Correlative studies including prostate tissue, blood (metabolic parameters), saliva and feces (microbiota) will be performed. Conclusion: Centers in Switzerland, Germany and France (GETUG) will recruit patients for this study. If positive, these results could help elucidate the role of metformin in CaP and determine the design of a subsequent phase III trial. Clinical trial information: NCT02945813.

299 Background: The need for validated circulating biomarkers is well recognised in advanced prostate cancer (PCa). Circulating biomarkers evaluating plasma cell-free nucleic acids and circulating tumour cells are being investigated for their clinical utility. There has been a lack of consensus with regards to analyses, reporting and clinical effectiveness of these biomarkers. A consensus meeting was held to address these issues. Methods: A multi-disciplinary panel comprising 18 international prostate cancer experts (including surgeons, medical and radiation oncologists) were consulted prior to the consensus meeting. Four key areas relating to the field of circulating biomarkers were deemed important for discussion: 1) The current utility of circulating biomarkers in 2017; 2) The clinical needs for circulating biomarkers in PCa; 3) The most pressing blood-based molecular assays required; and 4) The steps necessary for developing circulating biomarkers. Using a modified Delphi process, 50 consensus questions were pre-defined for the panel to answer by voting anonymously but publicly at the consensus meeting. Results: A consensus was declared (i.e. ≥ 75% of panellists who did not vote ‘unqualified’ or ‘abstain’ chose the same opinion) in 12/50 (24%) questions. A further 8/50 (16%) of replies were close to reaching consensus (≥ 60% of panellists choosing the same answer). The panel agreed that there is a very high and urgent unmet need for predictive biomarkers, with consensus that DNA repair biomarkers in particular are needed urgently. Metastatic PCa was identified as having the highest clinical need for development of biomarkers to measure response and as surrogate endpoints. Panellists unanimously voted that reproducibility validation studies are of paramount importance. The consensus panel also predicted that cfDNA will impact practice by 2020. Conclusions: This expert consensus identified the need for clinical trials of validated circulating biomarkers to develop predictive, response and surrogacy assays. These could have major clinical and healthcare economic implications, minimizing over-treatment and allowing the delivery of more precise patient care.

9518 Background: The benefits of BRAF + MEK inhibition (dual combo) in pts with BRAF V600-mutant ( BRAFV600) melanoma are known. Preclinical data supports inhibiting CDK 4/6 and BRAF + MEK (triple combo) to improve antitumor activity. We report safety and preliminary efficacy from a phase 1b/2 study (NCT01543698) of encorafenib (ENCO; a selective BRAF kinase inhibitor), binimetinib (BINI; a MEK inhibitor), and ribociclib (RIBO; a CDK 4/6 inhibitor). Methods: Phase 1b of this open-label, multicenter study enrolled pts with confirmed BRAFV600advanced solid tumors. Escalating doses of RIBO 100 mg-600 mg QD for 3 wk on/1 wk off were administered with ENCO 200 mg QD + BINI 45 mg BID in successive cohorts (6 pts each) until the maximum tolerated or recommended phase 2 dose (RP2D) was reached. Due to potential pharmacokinetic interactions with RIBO, the ENCO dose was lower than the dual combo RP2D (450 mg QD). Dose escalations followed an adaptive Bayesian model. In phase 2, the triple combo was tested in pts with BRAFV600melanoma naïve to prior BRAF inhibitor treatment; the primary endpoint was objective response rate (ORR) per RECIST v1.1. Results: In phase 1b (n = 21), no dose-limiting toxicities were reported and the triple combo RP2D was ENCO 200 mg QD + BINI 45 mg BID + RIBO 600 mg QD. ENCO AUC was slightly lower than at the dual combo RP2D. In phase 2 (n = 42), 59.5% pts had an ECOG PS of 0 and 43% of pts had elevated lactate dehydrogenase. The most common (≥5%) grade 3/4 toxicities were neutropenia (26.2%), increased alanine transaminase (14.3%), diarrhea (7.1%), and anemia (7.1%). Ten pts (23.8%) discontinued treatment due to an AE, of which 4 were increased transaminases. The confirmed ORR was 52.4%, including 4 complete responses, 18 partial responses, and 15 pts with stable disease. Median duration of exposure in phase 2 was 9.1 mo (range, 0.0-21.6). Median progression-free survival was 9.0 mo (95% confidence interval, 7.0-11.1). Conclusions: Triple therapy with ENCO + BINI + RIBO in this small trial of pts with high disease burden was associated with responses in over half of pts and some evidence of increased toxicity. Clinical trial information: NCT01543698.

5057Background: Ra-223 is an alpha emitter that selectively targets BM. Ra-223 is an approved treatment option for CRPC patients (pts) based on a significant improvement in overall survival. The pivotal phase III ALSYMPCA trial did not mandate monitoring of antitumor activity by imaging. We aimed to describe the imaging response in pts treated with Ra-223. Methods: Retrospective evaluation of computed tomography (CT) and bone scintigraphy (BS) of consecutive CRPC pts treated with Ra-223. All patients had scans done at baseline. Patients were treated with Ra-223 in 8 centers across 3 countries. Therapy consisted of standard Ra-223 administration (50 kBq q4 weeks for up to 6 injections). Results: A total of 127 pts were included (median age 72), of which 68% (n = 86) were treated with Ra-223 post docetaxel chemotherapy. A total of 20% (n = 26) of patients received concomitant abiraterone or enzalutamide. 52% (n = 66) patients completed the planned 6 injections. Clinical benefit (improvement of skeletal pain...

296 Background: Increased availability of treatment options in CRPC requires improved biomarkers to optimize decision making for therapeutic sequencing. Despite evidence for the value of CTCs in assessing prognosis and response to treatment, their use in clinical practice is not widely implemented. Clinicians rely on PCWG2 criteria based on PSA, clinical and radiological criteria although these are only inconsistently used in clinical practice. We evaluated the trends for clinical decision-making by physicians treating CRPC. Methods: An online questionnaire was distributed to physicians treating PC from the UK, Switzerland and Australia. Questions on clinical practice, familiarity with progression criteria, use of CTCs and clinical-decision making were formulated. Results: 111 participants replied. Most (84.7%) were oncologists treating ≥ 50 patients per year (65.3%). Although only 39.6% usually used PCWG2 in clinical practice, 74.5% considered PSA, bone scans and CT to be useful for monitoring disease. 55.6% considered PSA to be an important biomarker. A minority were able to identify PSA (41.4%) and bone scan (39.4%) progression criteria by PCWG2. On average, more physicians discontinued cabazitaxel (28%) than docetaxel (10.4%) before cycle 4. Similar number of cycles were given to bone only disease compared to RECIST evaluable patients. Clinical progression was most important for switching treatment for most physicians (90.5%), followed by RECIST (71.6%), bone scan (47.7%), CTC (23.2%) and PSA (21.1%). The main challenge associated with the use of CTCs was the access to technology (84.7%). Most respondents (92%) would not stop therapy with rising PSA but falling CTC counts; most (88.8%) would not stop with declining PSA but rising CTCs. Although 50% acknowledged the prognostic value of CTCs, only 33% would use them to guide decision-making. Conclusions: A significant number of physicians discontinue treatment before 12 weeks. Most physicians rely on clinical progression for decision-making. Knowledge of PCWG2 response and progression criteria is generally suboptimal. Greater physician awareness, access to technology and further evidence and will be required for the implementation of CTCs as a routine biomarker in CRPC.

187 Background: VT-464 is an oral, non-steroidal inhibitor of CYP17-L and an antagonist of androgen receptor (AR) variants F876L and T877A which are associated with resistance to enzalutamide (ENZ) and abiraterone/prednisone (AA), respectively. INO-VT-464-CL-001 is a Phase (Ph) 1/2 study of VT-464 in treatment-naïve (TN) and treatment-failure (TF) patients with CRPC. Results are reported for Ph 1 (TN patients) and early results from Ph 2 patients. Methods: Phase 1: safety, tolerability, PK and initial efficacy (PSA and steroid concentrations) in M0 and M1 TN patients in escalated dose-cohorts from 50 to 600 mg bid in 28-day continuous dosing cycles. Phase 2: preliminary efficacy in M0 and M1 TN and TF (post-AA, -ENZ, and/or CHEMO) patients at 450 mg bid. Results: In Ph 1, 26 TN patients received VT-464 at 50 mg bid (n=1), 100 mg bid (n=1), 200 mg bid (n=4), 300 mg bid (n=8), 450 mg bid (n=9) and 600 mg bid (n=3) with 2 patients currently on study (15 and 29 months). Another 10 TN patients received VT-464 in Ph 2 at 450 mg bid. Most Ph 1 adverse events (AEs) were grade 1 or 2 and not considered drug related. There were 18 grade 3 AEs and 1 grade 5 AE considered not related to study drug, plus 4 grade 3 AEs (vasovagal/syncope) considered at least possibly related. For a single oral 450 mg dose, t½ was 6.8±0.8h (mean±SEM), Cmax was 8.6±1.2uM and Tmax was 3.4±0.7h. 19 of 26 Ph 1 and Ph 2 TN patients who received from 300 to 600 mg bid had PSA responses (6 PSA30%, 2 PSA50% and 1 PSA90% response). Preliminary PSA responses in Ph 2 TF patients included a PSA90% response in a prior-ENZ pre-chemo patient and a PSA50% response in a prior-ENZ and -chemo patient. No mineralocorticoid excess syndrome (MES) or changes in ACTH response or LFTs were observed. Plasma testosterone concentrations were reduced to near or below the limit of quantification in most patients at ≥ 450 mg bid, with normal progesterone and cortisol concentrations. No supplemental steroids were used. Conclusions: Clinical results at the doses evaluated support VT-464 CYP17 L-selectivity. The PSA50% and PSA90% responses in 2 of 7 prior Xtandi patients, combined with a lack of MES despite no supplemental steroids, warrants further investigation in the ongoing Ph 2 study, particularly in prior ENZ and AA patients. Clinical trial information: NCT02012920.

180 Background: Advanced prostate cancer (APC) is a molecularly heterogeneous disease, with evidence of clonal evolution that could be responsible for resistance to treatment. About 90% of patients (pts) with APC have bone metastases. The acquisition of a bone marrow biopsies (BMBs) is a safe and feasible technique for obtaining tissue, with a low rate of complications. We hypothesized that pre-biopsy clinical variables may increase the success rate of BMBs in APC. Methods: Standard BMBs of the iliac crest were performed in APC pts between October 2011 and June 2013. All pts signed ethics approved consent. In the control cohort (n=10) BMBs were collected in pts with normal CT and bone scan appearance. Minimum, maximum, and mean Hounsfield Units (HU) of the iliac crest on pre-biopsy CTs were determined. Clinical and laboratory variables were collected from the electronic record system. Biopsies were defined as containing 50 or more or 1 to 50 malignant cells or none (negative). Univariate analysis was performed to determine variables associated with biopsy positivity with 50 or more cells. For variables with p value

70 Background: We aimed to establish a simple prognostic score for men with mCRPC treated with abiraterone following docetaxel and explored incorporation of the neutrophil/lymphocyte ratio (NLR), a marker of host inflammation with prognostic value in many solid tumors. Methods: To develop the model, clinical and laboratory factors for 185 men treated at Royal Marsden were included in a univariable Cox regression analysis. Statistically significant variables were dichotomized using an optimal cut-off chosen by selecting the highest c-index among three potential cut-offs with high Hazard Ratios (HR). All significant variables in univariable analysis were analyzed using multivariable Cox analysis. One risk point was assigned for each variable with a P value of 2.0 x ULN (HR 1.7, P=0.005), LDH >1.5 x ULN (HR 3.4, P5 (HR 1.5, P=0.033) were associated with worse OS in the multivariable analysis. Outcomes for three risk groups using these 5 factors are presented in the table. The c-index was 0.73 (95% CI 0.65 - 0.80) for the prognostic score. Patients with NLR >5 at baseline and whose NLR was ≤5 within four weeks of treatment also had longer median survival (15.1 months) than those with NLR >5 at baseline that remained high (median OS 7.6 months, HR 0.48, 95% CI 0.25-0.93, P=0.029). Conclusions: This initial simple risk score provides good prognostic and discriminatory accuracy for men with mCRPC. Data from the validation cohort will be presented. [Table: see text]

5049^ Background: Both Cbz and AA have demonstrated significantly improved survival in randomized Ph 3 studies in pts with mCRPC and progressive disease after D treatment. Cbz and AA have established non-overlapping adverse event (AE) profiles. A Ph 1/2 study was initiated to investigate the combination of Cbz + AA for the treatment of mCRPC (NCT01511536). Methods: Pts with progressive mCRPC after D were enrolled. The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz + AA (Ph 1), and the PSA response rate (RR) with this combination (Ph 2). Secondary endpoints included AEs, pharmacokinetics (PK) and efficacy. All pts received oral AA 1000 mg QD and P 5 mg BID. In Ph 1, pts received 1 of 2 dose levels (DL) of Cbz (20 and 25 mg/m2 IV Q3W) according to a 3+3 design. A 2-cycle DLT observation period was used. Here, we report results of Ph 1. Results: Ten pts were enrolled in Ph 1; 9 were evaluable: 3 at DL1 and 6 at DL2 completed 2 cycles without DLTs (total number of cycles = 46). In general, AEs were Grade (Gr) 1/2; the most frequent all-Gr AEs by pt cycle were asthenia (39%), diarrhea (37%; Gr 3 in 1 pt), back pain (26%), nausea (20%), constipation (20%), anemia (17%), decreased appetite (17%) and fatigue (15%; Gr 3 in 2 pts). In the safety population, 0/3 pts at DL1 and 2/7 pts at DL2 experienced Gr 3–4 neutropenia. The MTD was established at the full approved doses of both drugs (Cbz 25 mg/m2/AA 1000 mg). In 6 pts evaluable for PK (DL1 and DL2), median Cbz clearance (coefficient of variation %) was similar at cycle 1 (Cbz alone: 28.9 L/h/m2 [11%]) and cycle 2 (Cbz + AA coadministration: 28.6 L/h/m2 [42%]). In 9 evaluable pts, 55% PSA RR was observed. Conclusions: In this Ph 1 study, Cbz in combination with AA appeared to have a manageable safety profile. Gr 3–4 neutropenia was observed in 2 of 10 patients. Daily AA treatment did not affect Cbz clearance; Cbz exposure was comparable to previous studies of Cbz + P treatment. The Ph 2 portion is ongoing at the established MTD. Detailed safety, PK and preliminary efficacy data (Ph 1) will be presented. Clinical trial information: NCT01511536.

5052 Background: EZN-4176 is a third generationLNA-ASO that binds the ligand binding domain of AR mRNA resulting in full length AR mRNA degradation and decreased AR protein expression. Methods: Patients (pts) (performance status ECOG≤1) with progressing CRPC were eligible; prior abiraterone and enzalutamide treatment were allowed. EZN-4176 was administered as a weekly (QW) one-hour intravenous infusion. The starting dose was 0.5 mg/Kg with a 4-week dose-limiting toxicity (DLT) period. After determination of the DLT and the maximum tolerated dose (MTD) for weekly administration, a fortnightly schedule (Q2W) was initiated; a 3+3 modified Fibonacci dose escalation design was pursued. PD studies evaluated AR expression in tissue utilizing antibodies to the amino and carboxy-termini of the AR. Results: 22 pts were enrolled (median age 70.6 years, range 59 – 84 years). One pt was treated with the Q2W schedule. Two DLTs (G3/G4 ALT/AST elevation) occurred at 10 mg/Kg, which was therefore identified as the MTD for the weekly schedule. Multiple pts treated at 6.5 and 10 mg/Kg (5/9 pts, 55%) developed ≥G2 ALT and/or AST elevation after the first cycle requiring dose reduction and treatment delay. The most frequent adverse events (AEs) all-grades were fatigue (21/22 pts, 95.4%), nausea (10/22 pts, 45.4%), constipation (8/22 pts, 36.3%), AST (8/22 pts, 36.3%) and ALT (10/22 pts, 45.4%) elevation. The most frequent G3/4 AEs were AST (4/22 pts, 18.1%) and ALT (5/22 pts, 22.7%) elevation. Maximum PSA and circulating tumor cells (CTCs) declines are summarized below. There were no objective soft tissue responses. PD studies did not document any knockdown of AR expression Conclusions: EZN-4176 has limited antitumour activity in CRPC at its MTD for weekly administration. Safety, PK, PD and efficacy data will be presented. Clinical trial information: NCT01337518. [Table: see text]

4511 Background: AZD3514 is a first in class, orally bio-available drug that inhibits androgen-dependent and –independent androgen receptor (AR) signaling through two distinct mechanisms; inhibition of ligand-driven nuclear AR translocation and down-regulation of AR levels. Methods: A rolling six design was employed initially using a once a day (QD) schedule (A). PK assessments led to a change to twice daily (BD) dosing (B) to increase exposure. PK profiles were studied over 96 hours after a single dose and over 24 hours at start of/following 21 days continuous dosing. PD analyses included PSA and CTC quantification. Results: 49 CRPC patients (pts) have been treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000mg (QD). 2000mg BD was considered non-tolerable due to multiple grade 2 toxicities (nausea [N], vomiting [V], fatigue). No adverse events (AEs) met the DLT definition. The most frequent drug-related AE’s were N; G1/2 36/49 (73%), G3 2/49 (4%) and V; G1/2 24/49 (49%) & G3 3/49 (6%). N/V were managed with oral anti-emetics. Dose proportional increases in plasma concentrations were observed following a single dose. Geometric mean (%CV) Cmax and AUC at MTD were 9,608 (38.5) ng/mL and 61,734 (40.6) ng.hr/mL, respectively. Compared with single dose continuous dosing led to a mean decrease of 26% in exposure. Maximum PSA and CTC declines are summarized below. Objective soft tissue responses per RECIST1.1 were observed in 2/26 (8%) pts. One pt with abiraterone resistant disease remained on study for 19 months. At 6 and 12 months 21 (43%) and 8 (16%) pts remained on study without evidence of bone or soft tissue progression, respectively. Conclusions: AZD3514 has antitumor activity in patients with advanced CRPC. Clinical trial information: NCT01162395. [Table: see text]