PSMA PET SCANNING AND THERANOSTICS IN PROSTATE CANCER KEVIN TRACEY, MD, FRCPC PRECISION DIAGNSOTIC IMAGING REGIONAL PET/CT CENTRE

DISCLOSURES/CONFLICTS NONE

OBJECTIVES Understand current diagnostic role of PET/CT scanning in Prostate Cancer Describe new tracers and techniques Understand unique role of PSMA agents Understand principle of Radiotheranostics and Personalized medicine Describe current and future PSMA based therapies

INTERACTION! Please rate your current knowledge of PSMA PET Scanning and Theranostics in Prostate Cancer: A) Poor B) Fair C) Good D) Very Good E) Excellent 4

POSITRON EMISSION TOMOGRAPHY Nuclear Medicine imaging technique (New and Clear) Functional /Molecular Imaging versus Anatomical Imaging Fusion imaging available with PET/CT and PET/MRI

Normal coronal 18F-NaF PET/MR images representing (from left to right) PET maximum-intensity projection, PET coronal slice, T1-weighted MR image, and fusion of PET with MRI. Liza Lindenberg et al. J Nucl Med 2016;57:111S-116S (c) Copyright 2014 SNMMI; all rights reserved

WHAT IS PET? n ~1-3mm b + 511KeV Positron travels 1-3mm (depending on energy) before annihilation. 511KeV b - Annihilation process: - Energy (photons are 511KeV). Simultaneous detection of two 511KeV photons --> event along line between detectors. PET scanner detects both 511 KeV photons simultaneously, in coincidence.

WHAT IS PET? n ~1-3mm b + 511KeV Effects of positron range: 511KeV b - Function of emitted positron energy 18 F E max = 0.6MeV 15 O E max = 2.1MeV Therefore: 18 F has better resolution Fundamental resolution limit: ~2mm

WHAT IS PET? Each detector can be tested for coincidence against many detectors simultaneously.

WHAT IS PET? You start with Positron emitting tracers, such as: Radionuclide Half-Life 11 C 20.4 min 13 N 9.96 min 15 O 2.07 min 18 F 109.8 min 68 Ga 68 min 82 Rb 1.27 min Tracer production is integral to PET imaging: Short half-life

18 F-FDG Fluorine can substitute for -H or -OH in biologically active molecule [ 18 F]2-Fluoro-2-deoxy-D-glucose HO HO HO 18 F O OH Structure of [ 18 F]FDG

69-y-old man with castration-resistant metastatic prostate cancer before (A and B) and after (C and D) treatment with docetaxel. Hossein Jadvar J Nucl Med 2016;57:25S-29S (c) Copyright 2014 SNMMI; all rights reserved

CURRENT PET/CT Hallmark of cancer cells is the Warburg effect: increased glycolysis even in the presence ofoxygen 18 F-FDG images cancer on this basis Limited use in Prostate, Thyroid and Breast Cancer Need for more sensitive and specific tracers

NEW TRACERS IN PROSTATE CANCER 11 C-Acetate -Substrate in energy metabolism in cancer cells -Limited use/difficult to supply 18 F-Choline -Inorporated into cell membrane proliferating cancer cell -Lower sensitivity/specificity 18 F-NaF -Bone metastases only 18 F-Fluciclovine ( Axumin ) - amino acid analog (glutamine)

71-y-old patient who had suspected PC (prostate-specific antigen level, 11.4 ng/ml) and was referred for 18F-choline PET/CT. 18F-choline PET/CT showed right-side focal uptake in prostate, indicating PC. Biopsy proved PC (Gleason score, 4 + 5 = 9). Sascha Nitsch et al. J Nucl Med 2016;57:38S-42S (c) Copyright 2014 SNMMI; all rights reserved

PSMA Prostate Specific Membrane Antigen Excellent target antigen for prostate cancer Highly and specifically expressed on the surface of prostate cancer cells at all tumor stages Neovasculature of PCa also expresses PSMA Expression regulated by the Androgen Receptor Expression on cell surface increased with AR inhibition

PSMA

PSMA PSMA-11 ligand labelled with 18 F or 68 Ga 68 Ga-PSMA-11 or 18 F-PSMA ligands Low level expression in brain, kidneys, salivary glands and small intestine Rises with de-differentiation and in metastatic and hormone refractory cancers

68 GA-PSMA IN PCA SCENARIOS Screening Therapy for Localized Prostate Cancer Metastatic Disease

SCREENING Screening and stratification in patients with no diagnosis of cancer Identify significant vs. nonsignificant cancer Directing biopsy PET/MR with US

Figure 2 68 Ga-PSMA PET MRI of a 50-year-old patient who had a rising serum PSA value (16 ng/ml at imaging) and two tumour-negative previous biopsy samples Maurer, T. et al. (2016) Current use of PSMA PET in prostate cancer management Nat. Rev. Urol. doi:10.1038/nrurol.2016.26

THERAPY FOR LOCALIZED PROSTATE CANCER Staging:? mets present? pelvic nodes positive :? adjust XRT field Evaluate after definitive Sx /XRT therapy identify early local recurrence

64-y-old man with history of PCa treated by radical prostatectomy 4 y earlier and current biochemical recurrence (PSA, 0.61 ng/ml). Liza Lindenberg et al. J Nucl Med 2016;57:111S-116S (c) Copyright 2014 SNMMI; all rights reserved

METASTATIC DISEASE RISING PSA POST THERAPY Oligometastatic disease: resection or stereotactic XRT Diffuse Mets Distribution of mets: low vs high risk patients Response to therapy

68Ga-PSMA-11 PET/CT (A and B) and PET/MRI (C and D) of patient with recurrent PCa. Images show potential of MRI to clarify even moderate PSMA tracer accumulations as visible on PET/CT (arrow, A); although there is no correlation on CT, arrows in D indicate pathologic MRI signals suggesting bone metastases. Ali Afshar-Oromieh et al. J Nucl Med 2016;57:79S-89S (c) Copyright 2014 SNMMI; all rights reserved

First-in-human 68Ga-SRV171 PSMA PET/CT imaging demonstrating extensive and excellent tracer uptake in soft-tissue (lymph node) and skeletal metastases (arrows). Harshad R. Kulkarni et al. J Nucl Med 2016;57:97S-104S (c) Copyright 2014 SNMMI; all rights reserved

THERANOSTICS Developing molecular diagnostic tests in tandem with targeted therapeutics DIAGNOSIS AND THERAPY PERSONALIZED MEDICINE RADIOTHERANOSTICS

RADIOTHERANOSTICS NaI (I-131 RADIOIODINE) 177 Lu-PSMA 225 Ac-PSMA

RADIOTHERANOSTICS I-131 RADIOIODINE The original theranostic and radiotheranostic GRAVES AND OTHER HYPERTHYROIDISM THYROID CANCER PRIMARY AND METASTATIC Serum TG vs PSA post Rx

PSMA PET SCANNING AND RADIOTHERANOSTICS : IS PROSTATE CANCER THE NEW THYROID CANCER?

RADIOTHERANOSTICS IN PCA Rising PSA post treatment = metastatic disease mcrpc /Bone mets: 223 Ra Mixed Osseus and Non-osseus Mets

RADIOTHERANOSTICS IN PCA 177 Lu-PSMA Beta emitter like I-131 Endoradiotherapy Bone marrow suppression Salivary glands- dry mouth Radiation precautions

Between April 2013 and April 2016 119 mcrpc patients median age: 71 + 7 y mean Gleason score, 8 + 1 300 cycles of PRLT

Biodistribution and dosimetry results for normal organs in patients treated with different PSMA radioligands (median uptake in percentage injected activity [%IA]). Harshad R. Kulkarni et al. J Nucl Med 2016;57:97S- 104S (c) Copyright 2014 SNMMI; all rights reserved

Complete remission of disease and 100% decline in serum PSA, sustained for over 4 mo after PRLT. (A) Numerous 68Ga-PSMA avid skeletal metastases on PET/CT maximum-intensity-projection image before PRLT. (B D) Excellent uptake on 177Lu images during first treatment (B, whole-body anterior image 20 h after injection) (C and D, SPECT/CT images 41 h after injection). Harshad R. Kulkarni et al. J Nucl Med 2016;57:97S-104S (c) Copyright 2014 SNMMI; all rights reserved

(A) Serial 177Lu-PSMA whole-body images obtained around 20 h after injection during (from left to right) first to seventh PRLT cycles. Harshad R. Kulkarni et al. J Nucl Med 2016;57:97S-104S (c) Copyright 2014 SNMMI; all rights reserved

The survival data were analyzed in 104 patients Over a follow-up period of 34 mo (median, 19 mo), 26 patients died (25%) The median overall survival has yet to be reached. Progression-free survival from the commencement of therapy was estimated to be 10.7 mo.

Kaplan Meier curves showing overall (A) and progression-free (B) survival, according to RECIST 1.1, in 104 patients (observation period, 34 mo). Harshad R. Kulkarni et al. J Nucl Med 2016;57:97S-104S (c) Copyright 2014 SNMMI; all rights reserved

Between February 2014 and the end of July 2015, 145 patients (median age, 73 y; range, 43 88 y) mcrpc treated with 248 cycles of 177Lu-PSMA-617 12 nuclear medicine centers throughout Germany.

Conclusion: The present retrospective multicenter study of 177Lu-PSMA-617 RLT demonstrates favorable safety and high efficacy exceeding those of other third-line systemic therapies in mcrpc patients

RADIOTHERANOSTICS IN PCA 225 Ac-PSMA Alpha emitter like 223 Ra Low toxicity to marrow/other organs Minimal radiation precautions? More effective

68Ga-PSMA-11 PET/CT scans of patient A. Pretherapeutic tumor spread (A), restaging 2 mo after third cycle of 225Ac-PSMA-617 (B), and restaging 2 mo after one additional consolidation therapy (C). Clemens Kratochwil et al. J Nucl Med 2016;57:1941-1944 (c) Copyright 2014 SNMMI; all rights reserved

68Ga-PSMA-11 PET/CT scans of patient B. In comparison to initial tumor spread (A), restaging after 2 cycles of β-emitting 177Lu-PSMA-617 presented progression (B). Clemens Kratochwil et al. J Nucl Med 2016;57:1941-1944 (c) Copyright 2014 SNMMI; all rights reserved

FUTURE DEVELOPMENTS Will Rogers Phenomenon and PSMA: Worst patients in one group are recategorized as best patients in another improving outcomes in both groups Highest risk local disease recast as low-volume metastatic patients on basis of PSMA scan

FUTURE DEVELOPMENTS Personalized treatment plans Differentiate indolent from aggressive Pca Eliminate Salvage XRT Monitor response to therapy Combine with established therapies and earlier

SUMMARY PSMA SCANNING IS THE NEWEST TOOL IN DIAGNOSING AND TREATING PROSTATE CANCER POTENTIAL DIAGNOSTIC USE AT ALL STAGES OF DISEASE CHANGING OUR APPROACH TO PROSTATE CA AT ALL TREATMENT DECISION POINTS WITH RADIOTHERANOSTICS IS A NEW TOOL TO TREAT RESIDUAL/RECURRENT AND METASTATIC DISEASE IN A PERSONALIZED PLAN

INTERACTION! After this presentation, please rate your knowledge of PSMA PET Scanning and Theranostics in Prostate Cancer: A) Poor B) Fair C) Good D) Very Good E) Excellent 73

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