1269.79] vs PBO:2.36 ng/mL [range 0.02; 2254.50]). Lastly, AAP significantly delayed med time to PSA progression as compared to PBO (33.2 mo vs 7.4 mo, respectively; HR: 0.3, p < 0.0001) and the time to PSA progression strongly correlated with rPFS (Kendall’s tau¼ 0.9211) and OS (Kendall’s tau¼ 0.666).
Conclusions: Treatment of high-risk mHSPC with ADTþAAP demonstrates a signifi-cant depth of PSA response that strongly correlates with long-term outcomes of rPFS and OS.
Clinical trial identification: NCT01715285.
Editorial acknowledgement: Editorial assistance for this poster was provided by Ann C Sherwood, PhD, and editorial assistance was funded by Janssen Research and Development. Legal entity responsible for the study: Janssen Research and Development. Funding: Janssen Research and Development.
Disclosure: K.N. Chi: Institutional funding: Janssen for the study; Grant funding: Astellas, Bayer, Sanofi Janssen; Personal fees: Astellas, Bayer, Sanofi, Essa, Roche. M. Ozguroglu: Honoraria: Janssen, Sanofi. A. Rodriguez Antolin: Consulting services, Expert testimony: Astellas, Bayer, Janssen. S. Feyerabend: Advisory boards: Janssen, Boehringer Ingelheim Pharma, Aventis, Honorarium: Janssen, Travel and accommo-dation expenses: Aventis. L. Fein: Grant support, Personal fees: Novartis, Pfizer, Roche, Merck, Merck Sharp & Dohme; Grant support: Janssen, AbbVie. B.Y. Alekseev: Personal fees: Janssen, Pfizer, Merck, Roche, Sanofi. A. Protheroe: Consulting, Advisory roles, Travel, accommodations, and expenses: Ipsen, Bayer, Roche, Bristol-Myers Squibb, Merck; Research funding: Merck. G. Sulur, S. Li, P. De Porre, N. Tran, S.D. Mundle: Employee, Stock Owner: Janssen Research & Development. K. Fazazi: Advisory boards; Honoraria: Janssen, Astellas, Sanofi, and Bayer. All other authors have declared no conflicts of interest.
798PD In-depth assessment of metastatic prostate cancer with high tumour mutational burden N. Mehra1 , J. van Riet2 , M. Smits1 , H. Westdorp3 , M. Gorris3 , T. van Ee3 , M. van der Doelen4 , I. van Oort4 , M. Sedelaar4 , J. Textor3 , E. Cuppen5 , K. Grunberg6 , M.J.L. Ligtenberg7 , W. Zwart8 , A. Bergman9 , H.J.G. van de Werken2 , J. Schalken10 , I.J.M. de Vries3 , M.P. Lolkema11 , W.R. Gerritsen1 1
Medical Oncology, Radboud University Medical Centre Nijmegen, Nijmegen, Netherlands,2
Department of Cancer Computational Biology Center / Urology, Erasmus University Medical Center, Rotterdam, Netherlands,3
Department of Tumour Immunology, Radboud Institute for Molecular Life Sciences, Nijmegen, Netherlands, 4
Urology, Radboud University Medical Centre Nijmegen, Nijmegen, Netherlands,5 Center for Molecular Medicine, University Medical Center Utrecht / Hartwig Medical Foundation / Center for Personalized Cancer Treatment, Utrecht, Netherlands, 6
Department of Pathology, Radboud University Medical Centre Nijmegen, Nijmegen, Netherlands,7
Department of Pathology / Human Genetics, Radboud University Medical Center Nijmegen, Nijmegen, Netherlands,8
Oncode Institute / Division of Oncogenomics, Netherlands Cancer Institute (NKI-AVL), Amsterdam, Netherlands, 9
Division of Oncogenomics and Internal Medicine, Netherlands Cancer Institute (NKI-AVL), Amsterdam, Netherlands,10
Laboratory of Experimental Urology, Radboud University Medical Centre Nijmegen, Nijmegen, Netherlands,11
Medical Oncology, Erasmus University Medical Center / Center for Personalized Cancer Therapy, Rotterdam, Netherlands
Background:A comprehensive assessment of biopsies from metastatic prostate cancer (mPCa) patients (pts) may identify a molecular subset of pts susceptible for immune checkpoint (IC) blockade (ICB).
Methods:148 biopsies and germline DNA from 145 mPCa pts were whole genome sequenced (WGS) at an average of 114x and 38x. Tumour mutational (mut) burden (TMB) was defined as number of somatic single nucleotide variants and InDels per Mb of the genome, known mut signatures (Alexandrov, Nature 2013) extracted by non-negative least squares regression as well as recurrent mutations reported in mismatch repair (MMR) pts (Kim, Cell 2013). Selected pts with high TMB were further evaluated for; (a) MMR protein expression; (b) multiplex intratumoural (IT) immune cell phe-notyping (VECTRA); (c) multiplex IC expression (VECTRA); (d) 8-color flow cytome-try blood immune cell phenotyping, with high TMB pts compared with low TMB pts. Pts receiving anti-PD-1 ICB had additional immune phenotyping at C2, C3, C4 and at progression; 3 pts had post-progression biopsies analyzed.
Results:The median TMB was 2.9 (IQR 2.2 - 3.9); 12 pts (8.3%) had high TMB (>10 mut/Mb). In 11/12 pts with high TMB, corresponding MMR deficiency (MMRd) sig-natures (6, 15, 20 and 21) were identified. Recurrent mut in MMR genes were detected MSH2/MSH6, MSH3, MLH1; other recurrent mut were in POLE, and frameshift mut enriched (p < 0.001) in genes including TGFBR2, CLOCK, RPL22 and JAK1. Immunohistochemistry confirmed MMRd in 6/6 biopsies and in matched primary tis-sue in 5/5 evaluable pts. Five pts were referred for germline testing without MMR mut. A trend for increased IT CD3þ cells were seen in MMRd (p ¼ 0.06); no relation was found between TMB and tumour PD-L1 expression. Pts were treated with anti-PD-1 ICB, with PSA>50% decline of 57% of hTMB pts (n¼ 7), and a significant decline in circulating T-cell populations during ICB, including CD4þPD-1 þ (p ¼ 0.02) and CD8þPD-1 þ (p ¼ 0.007). Response rate, duration of response, genomic and immune correlates will be presented for pts with low and high TMB.
Conclusions:8% of mPCa pts display a high TMB with recurrent somatic mut in MMR genes and POLE. MMRd appears early in PCa evolution. High TMB pts witness a high response rate to monotherapy anti-PD-1 ICB.
Clinical trial identification:NCT01855477.
Legal entity responsible for the study:Radboud University Medical Center. Funding:This data and the underlying study have been made possible partly on the basis of the data that Hartwig Medical Foundation and the Center of Personalised Cancer Treatment (CPCT) have made available to the study.
Disclosure:N. Mehra: Advisory board: Janssen; Honoraria: Bayer, Astellas, Janssen, MSD, BMS; Research funding: Astellas, Janssen. M. van der Doelen: Research grant: Bayer, the Netherlands. I. van Oort: Funding: Astellas, Janssen, Sanofi, Bayer. M.J.L. Ligtenberg: Research funds, Consultancy: AstraZeneca. All other authors have declared no conflicts of interest.
799PD Phase I dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration resistant prostate cancer (mCRPC) S.T. Tagawa1 , S. Vallabhajosula2 , Y. Jhanwar2 , A. Hackett1 , C. Oromendia3 , M.J. Naiz4 , S.J. Goldsmith2 , D.M. Nanus5 , H. Beltran5 , A.M. Molina1 , B. Faltas1 , J. Sreekumar1 , J. Babich2 , K. Ballman3 , N.H. Bander4 1
Hematology and Medical Oncology, Weill Cornell Medical College, New York, NY, USA,
2
Radiology, Weill Cornell Medical College, New York, NY, USA,3
Department of Healthcare Policy & Research, Weill Cornell Medical College, New York, NY, USA,
4
Urology, Weill Cornell Medical College, New York, NY, USA,5
Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, NY, USA
Background: PSMA is selectively overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression in other organs. PC is radiosensitive with dose-response data. Dose-fractionation may allow delivery of higher total doses with less radioresistance than doses several weeks to months apart. Small molecule PSMA inhibitor ligands can be successfully radiolabeled and have been used for imaging and treatment, but no dose-escalation study has been performed. Methods: Progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/ enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies provided adequate organ function, ECOG performance status 0-2, and without preselection for PSMA expression were enrolled. Treatment was a single cycle of fractionated dose177
Lu-PSMA-617 on D1 and D15 starting at 7.4 GBq with planned escalation up to 22.2 GBq in modified 3þ 3 dose-escalation. Primary endpoint is determination of dose limiting tox-icity (DLT) and recommended phase 2 dose (RP2D) with secondary efficacy endpoints. Pre- and post-treatment 68Ga-PSMA11 PET/CT and post-treatment 177Lu-PSMA-617 imaging was performed in addition to standard serial CT and bone scans.
Results: 29 men with median age 70 (range 56-87), median PSA 98.9 (range 6-2222) were treated. 93% with bone, 25% node, 14% lung, 7% liver, 7% other visceral metasta-ses. 52% with at least 1 chemo, 45% >1 prior potent AR therapy, 17% with Ra223, 10 sip-T, 3% 177Lu-J591. No DLT was seen at any planned dose-level. With follow up ongoing, 41% with >50% PSA decline. Of 14 with paired CTC counts (CellSearch), 64% decreased, 14% stable, 14% increased (with 28.6% undetectable at 12 weeks). Adverse events include 55% xerostomia, 27.6% fatigue, 27.6% nausea, 27.6% thrombo-cytopenia, 20.7% anemia, 17.2% back pain. All had some PSMA uptake on imaging, with median (range) SUVmax 25 (4-119) bone, 32 (7-111) node, 10 (3-16) visceral. Conclusions: Dose-escalation of177Lu-PSMA-617 is safe up to 22.2 GBq per cycle with
fractionated dosing, with promising early efficacy and tolerability signals. Enrollment to the phase 2 study at RP2D will provide additional efficacy and toxicity data. Clinical trial identification: NCT03042468.
Legal entity responsible for the study: Weill Cornell Medical College. Funding: Weill Cornell Medical College, Prostate Cancer Foundation, National Institutes of Health.
Disclosure: All authors have declared no conflicts of interest.
800P The prognostic value of the proportion and subtype patterns of intraductal carcinoma of the prostate in patients with de novo metastatic prostate cancer: A propensity score matching study J. Zhao, J. Liu, G. Sun, P. Shen, J. Chen, X. Zhang, H. Zhang, Z. Liu, Y. Bao, Y. Yang, P. Zhao, K. Shu, H. Zeng
Department of Urology, Institute of Urology, West China Hospital, SiChuan Univer, West China Hospital, Sichuan University, Chengdu, China
Background: Intraductal carcinoma of the prostate (IDC-P) is an adverse prognostica-tor of prostate cancer (PCa). However, the role of IDC-P proportion and architectural patterns in patient outcome remain unclear.
Methods: Data of 644 de novo metastatic PCa (mPCa) patients between 2010-2017 were retrospectively analyzed. IDC-P was identified from 12-core prostate biopsy. IDC-P proportion were calculated. IDC-P were classified into two architectural pat-terns according to the 2016 WHO classification: pattern-1 (loose cribriform or micro-papillary) and pattern-2 (solid or dense cribriform). Propensity-score matching (PSM) was conducted to balance the baseline characteristics between patients with and without IDC-P. Kaplan-Meier curves and COX regression were utilized in survival analysis. The endpoints were castration-resistant PCa free survival (CFS) and overall survival (OS).
