Radioligand imaging & treatment of prostate cancer

Radioligand imaging & treatment of prostate cancer Christiaan Schiepers, MD, PhD University of California Los Angeles

CANM-CAMRT JOINT ANNUAL CONFERENCE MARCH 22-24, 2018 VANCOUVER, B.C. I do not have a financial interest, arrangement or affiliation including receipt of honoraria or expenses with a commercial organization that may have a direct interest in the subject matter of my presentation.

PROSTATE CANCER AFTER PRIMARY SURGERY Within 10 years up to one third of patients manifest recurrent disease OVERALL Biochemical recurrence free-survival Time since radical prostatectomy in years Walz J et al. BJU Int 2011 Thompson et al. AUA/ASTRO Guideline. J Urol. 2013

PROSTATE CANCER AFTER PRIMARY SURGERY 10 year risk of biochemical recurrence: 5% to 85% Dependent upon initial clinical and pathological characteristics Biochemical recurrence free-survival HIGH RISK ct3 = extra-prostatic extension Time since Radical Prostatectomy in years Walz J et al. BJU Int 2011

PSA level and Test Positivity. Radio-tracer Serum PSA 99m Tc-MDP > 7-10 ng/ml 18 F-FDG > 5 11 C- or 18 F-Choline > 2-3 11 C-Acetate > 1-2 11 C-Choline > 1-2 ng/ml/year PSA velocity 18 F-Fluciclovine >??? 68 Ga-PSMA-11 >???

Glutamate carboxy-peptidase 2 GCP-2 FOLH-1 PSMA

PSMA receptor Significantly over-expressed on prostate cancer cells Some primary prostate cancers do not express PSMA 10 2-10 3 fold 5-10% negative scans Expression is even more increased in mcrpc

Radio-ligands PSMA-11 can be labeled with 68 Ga Diagnosis PSMA-617 can be labeled with 177 Lu Therapy

Prostate Specific Membrane Antigen Type II transmembrane glyco-protein PSMA function in prostate cells is still unknown

PSMA RESEARCH DATES BACK TO 1970S Biology Imaging Therapy 1970 1980 1990 2000 2010 2020 LNCaP 7E11 Function 11 C 177 Lu 18 F 68 Ga NYS/Buffalo 7E11 (ProstaScint) Johns Hopkins/Georgetown Weill Cornell Heidelberg DCFPyl J591 PSMA11 PSMA617 PSMA1007

RADIOLIGANDS TARGET PSMA FOR IMAGING AND THERAPY PSMA (glutamate carboxypeptidase 2) Degree of expression correlates with the pathological grade and recurrence Internalization upon ligand binding PSMA-11 PSMA-617 PSMA-I&T Other probes: MIP1095 DCFBC DCFPyl PSMA1007 J591 mab 7E11 mab...

PSMA receptor expression Diagnosis & Staging

Radionuclide Gallium-68

CURRENT STATUS OF PSMA PET/CT Not an FDA or EMA approved probe for PET imaging PSMA PET/CT is standard of care in Australia, Israel, Germany, other European countries Most of current literature on 68 Ga-PSMA-11 (Heidelberg Compound) EAU guideline 2017: BCR at PSA >1 ng/ml: PET/CT is recommended using choline or PSMA (LE 2b, GR A). Multiple trials under way to establish accuracy and impact on management (e.g. NCT02940262, NCT02918357, NCT02919111)

PSMA PET ACCURATELY LOCALIZES BCR Detection rate correlates with PSA level Metaanalysis of 22 studies / >1000 patients Predicted detection rate (mean ± 95%CI) Detection rate is superior Metaanalysis of 53 studies / >1500 patients Detection rate (mean ± 95%CI) 48% at 0.2 56% at 0.5 70% at 1.0 ng/ml Perera et al. Eur Urol 2016 Chung et al. Am J Nucl Med Mol Imaging 2014

BIOCHEMICAL RECURRENCE - BCR 61 y/o patient, Gleason 7, s/p prostatectomy 2013 PSA rising to 0.5 ng/ml in 2017 (12 months doubling time) 68 Ga-PSMA-11 PET PET/CT cect salvage LND confirmed 3/12 positive LNs

PSMA PET INDUCES CHANGE IN MANAGEMENT A PROSPECTIVE UCLA TRIAL Scheduling PET/CT Report + DVD + 1 month TREATMENT + 3 to 6 months Pre-Scan Questionnaire Q1 Intended change Post-Scan Questionnaire Q2 Implemented change Late Follow-up Questionnaire Q3 or File review/contact INTENDED TREATMENT BEFORE PET/CT INTENDED TREATMENT AFTER PET/CT ACTUAL IMPLEMENTED TREATMENT Intended Implemented MANAGEMENT CHANGES 62 (61%) 54 (53%) Conversion to Focal Treatment / New Focal Treatment 40 (40%) 29 (29%) Conversion to systemic treatment 12 (12%) 13 (13%) Conversion to active surveillance 5 (5%) 7 (7%) Change in Systemic Treatment 5 (5%) 5 (5%) Calais et al. J Nucl Med 2018 Mar;59(3):434-441

PRIMARY STAGING 77 y/o patient, ipsa 7.1, GS 4+5=9, bone scan negative primary PCa, nodal metastases, bone metastases 68 Ga-PSMA-11 PET

p<0.001 p=0.002 PSMA PET DETECTS NODAL METASTASES AT PRIMARY STAGING 130 intermediate/high risk primary PCa 35 PET/CT, 95 PET/MR using 68 Ga-PSMA-11 standardized PLND with separated field histopathology Sens (%) Spec (%) PPV (%) NPV (%) Acc. (%) CT/MRI 42 86 56 77 72 PSMA-PET 75 99 96 90 92 Patientbased Fieldbased* Sens (%) Spec (%) PPV (%) NPV (%) Acc. (%) CT/MRI 28 97 60 89 87 PSMA-PET 76 99 94 96 96 Maurer,..., Eiber et al. J Urol 2015

INTEROBSERVER AGREEMENT IS SUBSTANTIAL 50 patient cases, 16 international readers Histopathology/imaging follow-up as reference standard * * * * * * * * T N Mb Mc *Fulfill predefined criteria: high or intermediate experience readers Fendler et al. J Nucl Med 2017

MI TNM CLASSIFICATION PROMISE Final diagnosis: mi T0 N0 M1a (PR, SD) b (oligo) Prostate Cancer Molecular Imaging Standard Evaluation Eiber, Fendler et al. J Nucl Med 2018 Mar;59(3):469-478

18 F-AXUMIN VERSUS 68 GA-PSMA Head-to-head comparison of 68 Ga-PSMA-11 PET/CT and 18 F-Fluciclovine PET/CT in a case series of 10 patients with prostate cancer recurrence. J Calais et al. J Nucl Med. 2017 Dec 14.

PSMA receptor expression Mapping for Radiation-Therapy

68 GA-PSMA PET/CT MAPPING OF EARLY BIOCHEMICAL RECURRENCE AFTER PRIMARY SURGERY IN 270 PATIENTS: IMPACT ON SALVAGE RADIOTHERAPY PLANNING J Calais - J Czernin M Eiber - WP Fendler - K Herrmann M Cao - N Nickols University of California Los Angeles Technical University of Munich Ludwig-Maximilians-University of Munich University of Essen J Nucl Med. 2018 Feb;59(2):230-237. doi: 10.2967/jnumed.117.201749. Epub 2017 Nov 9.

SALVAGE RADIATION THERAPY AUA / ASTRO GUIDELINE Rising PSA after radical prostatectomy without evidence for distant failure = Indication for salvage RT with / without ADT = Currently the only curative option Success depends upon: Absence of distant metastases Pre-RT PSA level the earlier the better: at 0.5 ng/ml, some say 0.1 ng/ml) Longer interval to biochemical recurrence predicts better response Gleason Score Tumor margins (positive predicts higher local recurrent disease) T,N stage (by pathology and by conventional imaging) Re-staging evaluation in a patient with PSA recurrence may be considered. (Option; Evidence Strength: Grade C) Stephenson et al. JAMA. 2004 Stephenson at al. J Clin Oncol. 2007 Thompson et al. AUA/ASTRO Guideline. J Urol. 2013

SALVAGE RADIATION THERAPY Clinical Practice SRT is commonly initiated in patients with PSA level < 1 ng/ml when conventional imaging is not sensitive for detecting recurrence. SRT target volumes are usually drawn in the absence of radiographic evidence of recurrent disease.

SALVAGE RADIATION THERAPY Current Guidelines : RTOG EORTC Canada Australia TV = Target Volume Michalski et al. RTOG guidelines IJROBP 2010

RADIATION-THERAPY TARGET VOLUMES CONTOURING GTV CTV PTV DOSIMETRY SIMULATION Limited by healthy tissues (OAR)

SALVAGE RT : RESULTS > 80% of patients show PSA decrease after SRT ~ 67% have undetectable PSA levels ~ 50% free from biochemical, clinical, or radiographic progression (20%-80% depending on existing clinical-pathologic features) CAVE : For high-risk patients, 5-year biochemical failure rate after SRT reaches 70% Approximately 15% of these patients die within 10 years Moghanaki et al. Cancer 2012 Zumsteg et al. J Clin Oncol. 2016

SALVAGE RT : RESULTS In field recurrence after salvage RT in CTV is low: 14% (1) Recurrence outside the CTV is common: 86% (1) First recurrence: Prostate bed: 4% (1); 5% (2) Lymph Nodes: 89% (1); 27% (2) Bone: 6% (1); 64% (2) (1) with 11 C-Choline PET-CT (2) with conventional imaging 11 C-Choline PET-CT recurrences (red = histologically confirmed) (1) Parker et al. IJROBP. 2017 (2) Jackson et al. BJU 2017

Eiber et al. JNM 2015 PET/CT USING PSMA Powerful tool to detect recurrence at an early stage (PSA<1) Displays new patterns of early recurrence (PSA<1) that we could not see before Detection rates ~50% for PSA < 0.5 ng/ml 68 Ga-PSMA PET/CT has thus the potential to guide and improve target volume delineations for SRT.

PATIENT POPULATION SRT CANDIDATES PSMA PET/CT Radical prostatectomy Biochemical recurrence No prior radiation therapy PSA < 1 ng/ml Databases from : Technical University of Munich (TUM; n=147) University of California Los Angeles (UCLA, n=47) Ludwig-Maximilians-University of Munich (LMU; n=40) University of Essen (n=36) Total N = 270

PRIMARY OBJECTIVES Where are the PSMA positive lesions located? In-field or Out-of-field? How often outside radiation treatment field? Do the contours cover the recurrences? Potential impact of PSMA PET/CT on SRT planning?

METHODS 1 consensus CTV on CT PSMA PET/CT Blinded by radiation oncologist Orange = Prostate CTV Green = Pelvic LN CTV

METHODS

METHODS

PATIENT CHARACTERISTICS Characteristics n = 270 Age at PET/CT, median (years) 67 ± 8 (range 43-90) Initial PSA before Surgery, median (ng/ml) 8.3 ± 22.2 (range 0.4-200) < 10 130 (48%) 10 < 20 46 (17%) 20 38 (14%) Unknown 56 (21%) Gleason Score 6 33 (12%) 7 135 (50%) 8 86 (32%) Unknown 16 (6%) Pathologic Primary Tumor Staging (pt) pt2 98 (36%) pt3 142 (52.5%) pt4 2 (0.7%) Unknown 27 (10%) Pathologic Regional LN Staging (pn) pn0 166 (61.5%) pn1 54 (20%) pnx 50 (18.5%) Positive Margin R0 152 (56.5%) R1 67 (25%) Unknown 51 (19%) NCCN Risk Group Low 4 (1.5%) Intermediate 36 (13.5%) High 163 (60.5%) N1 54 (20%) Unknown 13 (5%) ADT within 6 months prior to imaging 33 (12.5%) Time between surgery and PET/CT, median (months) 25 ± 45 (range 2-272) PSA value prior to PET/CT, median (ng/ml) 0.48 ± 0.25 (range 0.03-1)

PSMA PET/CT FINDINGS

PSMA PET/CT FINDINGS

INSIDE THE CTV

DISTAL EXTERNAL ILIAC RECURRENCE

EXTRA-PELVIC RECURRENCE

3D MAPPING OF RECURRENCES

3D MAPPING OF RECURRENCES 132/270 (49%) positive 68 Ga-PSMA PET/CT 52/270 (19%) at least one PSMA avid lesion not covered by consensus CTVs. 33/270 (12%) extra-pelvic metastases bone (23/270, 9%) 19/270 (7%) PSMA avid pelvic lesion(s) not covered by consensus CTVs without extrapelvic metastases perirectal LNs (16/270, 6%) distal external iliac LNs (9/270, 3%)

PSA LEVELS AND PSMA POSITIVITY 153 patients PSA < 0.5 (very low PSA group) 117 patients PSA > 0.5-1.0 (low PSA group) PSA < 1 0.5-1 < 0.5 N 270 153 117 PSMA + 132 49% 62 41% 70 60% p = 0.002 Outside of CTV 52 19% 20 13% 29 25% p = 0.4

TAKE HOME MESSAGES 68 GA-PSMA PET/CT MAPPING OF EARLY BIOCHEMICAL RECURRENCE AFTER PRIMARY SURGERY IN 270 PATIENTS: IMPACT ON SALVAGE RADIOTHERAPY PLANNING 68 Ga-PSMA PET/CT detected lesions outside the consensus target volumes in 20% of patients with early failure (PSA < 1) after surgery thus suggesting a major impact on SRT planning Most frequent lesions outside the CTV are in: bone, perirectal, distal external iliac nodes 68 Ga-PSMA PET/CT detected lesions inside the consensus target volumes in 30% of patients, suggesting a minor impact on SRT planning (dose boost) Overall, 68 Ga-PSMA PET/CT may impact SRT in half of patients with PSA < 1

PSMA receptor expression Radioligand Imaging and Therapy

Prostate Specific Membrane Antigen There are multiple PSMA ligands available PSMA-11 can be labeled with 68 Ga Diagnosis PSMA-617 can be labeled with 177 Lu Therapy

CLINICAL TRIALS AT UCLA PET/CT imaging BCR Primary Any 68 Ga-PSMA PET/CT for detection of recurrent prostate cancer after initial therapy (ongoing) 68 Ga PSMA PET/CT before prostatectomy in patients with newly diagnosed prostate cancer (ongoing) Change in management after 68 Ga PSMA PET/CT (initiation Q1 2018)

Radionuclide Lutetium-177

Rahbar et al. J Nucl Med 2017; Fendler et al. Oncotarget 2017 PSMA RADIOLIGAND THERAPY Reduces Serum PSA Levels Reduces Tumor Size Improves Pain and QoL

CLINICAL TRIALS AT UCLA mcrpc Radioligand Therapy PSMA-directed endoradiotherapy of castration-resistant Prostate Cancer (RESIST-PC). A phase II clinical trial. (started Q4 2017)

PATIENT #2 Age 71 yrs Diagnosis April 2016 Gleason 5 + 4 PSA 2000 ng/ml Multiple bone metastases ADT + Chemo 2016 PSA 8.5 ng/ml August 2016 ADT 2 nd G 2016-17 Bone scan PET/CT PSA 7-JUN-2017 23-OCT-2017 849 ng/ml

PATIENT #2 PET/CT 23-OCT-2017

PATIENT #2 PLANAR + SPECT/CT TREATMENT WITH 6 GBQ LU-177 ON 13-NOV-2017 177 Lu-PSMA-617 +4h 177 Lu-PSMA-617 +24h 177 Lu-PSMA-617 +48h 177 Lu-PSMA-617 +72h 68 Ga-PSMA-11 23-OCT-2017

PATIENT #2 TREATMENT WITH 6 GBQ LU-177 ON 13-NOV-2017 23-OCT-2017 Before Treatment 10-JAN-2018 After Treatment

SUMMARY 68 GA-PSMA IMAGING PSMA PET/CT provides superior tumor detection at biochemical recurrence (50% at PSA 0.5 ng/ml) leading to change in management in about 50% of patients PSMA PET/CT provides high accuracy for primary nodal staging of intermediate/high risk disease (75% SE, 99% SP); PET can be combined to improve mpmri Interobserver agreement is substantial after 1 hour reader training PROMISE criteria propose standardized reporting Outlook: Several ongoing trials aim at approval of imaging probes (DCFPyl, PSMA11 and MIP1095)

SUMMARY 177 LU-PSMA THERAPY Phase II trial started and ongoing at UCLA for mcrpc after failure of other treatments Approval for 100 patients under IND 28 patients enrolled, 2 had progressive disease after 1 cycle. Nobody has yet finished the trial of 4 cycles (1 per 8 weeks) No significant PSA change during the first 2 cycles One third of patients report subjective response