PSMA Targeted Therapies Professor Michael Hofman , MBBS, FRACP, - - PowerPoint PPT Presentation

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PSMA Targeted Therapies Professor Michael Hofman , MBBS, FRACP, - - PowerPoint PPT Presentation

Nov 10, 2022 273 likes •721 views

#APCCC2019 PSMA Targeted Therapies Professor Michael Hofman , MBBS, FRACP, FAANMS Molecular Imaging & Therapeutic Nuclear Medicine, Centre for Cancer Imaging Peter MacCallum Cancer Centre / The University of Melbourne @DrMHofman

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PSMA Targeted Therapies

Professor Michael Hofman, MBBS, FRACP, FAANMS

Molecular Imaging & Therapeutic Nuclear Medicine, Centre for Cancer Imaging Peter MacCallum Cancer Centre / The University of Melbourne @DrMHofman michael.hofman@petermac.org

#APCCC2019

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Disclosures

2 Research Support Endocyte (a Novartis company) Consulting none Honoraria/travel support Janssen, Sanofi Genzyme, Ipsen Stock ownership None Study Chair TheraP

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Prostate Specific Membrane Antigen (PSMA)

3

O’Driscott C et al, Br J Pharm 2016

doi:10.1111/bph.13576

#PSMA

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O’Driscott C et al, Br J Pharm 2016

doi:10.1111/bph.13576

THERANOSTICS

TARGETED THERAPEUTIC + DIAGNOSTIC COMPANION

radioactive small molecule targeting prostate specific membrane antigen (PSMA) highly over-expressed in prostate cancer

Pre-therapy PET/CT Post-therapy SPECT/CT

68Ga-PSMA-11

PET

177Lu-PSMA-617

SPECT

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targeted drug: “too smart”

nearby cells not expressing target

develop resistance

1mm path-length: cross-fire effect

all cells in 1mm radius targeted

Lutetium-177 (177Lu): short path-length beta emitter

mean path length 1mm, average penetration 0.3mm, 6.7 day half-life

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2014: high activity of small molecule (not Ab) targeting PSMA

Zechmann CM et al, Eur J Nucl Med Mol Imaging 2014, 14:1280-1929 Serial 124I-MIP-1095 PET

131I-MIP-1095

Best PSA response in 25 pt PSA ≥ 50% in 61%

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2015: retrospective data suggests high activity of 177Lu

Baum R et al, 3rd World Congress in Theranostics, John Hopkins Medical Centre, USA, March 2015

Best PSA Response in 37 patients

  • mCRPC. 177Lu-PSMA-I&T
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2015: 1st published report of 177Lu-PSMA617

Kratochwil et al, Eur J Nucl Med Mol Imaging 2015. May;42(6):987-8

DOI 10.1007/s00259-014-2978-1

2 cycles

177Lu-PSMA617

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Theranostics @ Peter Mac

Gastro-entero-pancreatic Neuroendocrine Tumours Prostate 600 400 200

No of therapies per year

177Lu-DOTATATE 177Lu-PSMA

1st PSMA therapy in Australia

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2015-8: 1st prospective phase II study @ Peter Mac

Remarkable responses in patients who progressed after conventional therapies

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75 pt screened for eligibility 50 enrolled Up to 4 cycles 177Lu-PSMA 50 included in analysis

Peter Mac Phase II Baseline characteristics & schema

Characteristic Median or N (%) Age (years) 71 Alkaline phosphatase (U/L) 131 PSA (ng/mL) 189.8 PSA doubling time (ng/mL/month) 2.6 ECOG performance status 1 2 20 (40%) 22 (44%) 8 (16%) Prior treatments Abiraterone or enzalutamide or both Docetaxel Cabazitaxel Docetaxel + abi / enza ± Cabazitaxel 45 (90%) 42 (84%) 24 (48%) 39 (78%)

median follow-up: 31.4 months

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Best PSA Response (N=50)

Hofman MS et al, ASCO GU 2019.

  • 100
  • 50

50 100 PSA Response % <30% ≥30% ≥50% Patients

PSA Response N (%) 95% CI ≥ 30% 37 (74%) 60 - 84 ≥ 50% 32 (64%) 50 - 77 ≥ 80% 22 (44%) 30 - 59

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13 EANM'18

IMAGE OF THE YEAR 2018 #PSMA

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Treatment-emergent adverse events

1 2 3 4 Dry mouth 29 (58%) 4 (8%) 0 (0%) 0 (0%) Lymphocytopenia 7 (14%) 13 (26%) 16 (32%) 0 (0%) Thrombocytopenia 11 (22%) 3 (6%) 4 (8%) 1 (2%) Fatigue 15 (30%) 3 (6%) 1 (2%) 0 (0%) Nausea 20 (40%) 4 (8%) 0 (0%) 0 (0%) Anaemia 3 (6%) 6 (12%) 5 (10%) 0 (0%) Neutropenia 6 (12%) 6 (12%) 3 (6%) 0 (0%) Bone Pain 5 (10%) 4 (8%) 0 (0%) 0 (0%) Vomiting 11 (22%) 2 (4%) 0 (0%) 0 (0%) Anorexia 8 (16%) 0 (0%) 0 (0%) 0 (0%) Dry eyes 4 (8%) 1 (2%) 0 (0%) 0 (0%) Renal injury* 4 (8%) 1 (2%) 0 (0%) 0 (0%) Weight loss 3 (6%) 1 (2%) 0 (0%) 0 (0%)

attributable to Lu-PSMA

*51Cr-EDTA GFR measured 3 months after completion of 177Lu-PSMA-617 in 28 pt demonstrated mean decline of -11.7 mL/min (95% CI -19 to -4)

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Hofman MS et al (unpublished)

75 pt screened for eligibility Up to 4 cycles 177Lu-PSMA 50 included in analysis 15 (30%) received further LuPSMA

PSA ≥50% response: 73%

Lu-PSMA re-treatment

#APCCC2019

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FDG PSMA

69yo progressed after docetaxel, enzalutamide, abiraterone & cabazitaxel

baseline

175 Gy after LuPSMA #1

PSMA PET baseline

16

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* LuPSMA * * * * * *

10 20 30 40 50 60 70 80 90 100

  • 10

10 20 30 40

months from Lu-PSMA PSA (ug/L)

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* LuPSMA * * * * * *

10 20 30 40 50 60 70 80 90 100

  • 10

10 20 30 40

months from Lu-PSMA PSA (ug/L)

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Cycle 2 Cycle 3 Cycle 4

  • 3 month FU

Cycle 2 Cycle 3 Cycle 4 3 month FU −2.0 −1.5 −1.0 −0.5 0.0

cycle 1

0.5

Mean difference from

Pain Interference

  • Pain Severity
  • 19

QoL

Brief pain inventory

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How do our results compare to others?

PSA response PSA ≥50% in 64%

Hofman MS et al

PSA ≥50% in 45% **

Rahbar K et al

N=50 N=145

46 pt had PSA follow-up less than 8 wk

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PSA ≥50% in 64%

Hofman MS et al

PSA ≥50% in 45%

Rahbar K et al

N=50 N=145

  • 100
  • 50

50

N=100 PSA ≥50% in 32%

Heck et al

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Is this patient suitable?

20 SUV PSMA

SUVmax 70

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FDG PET: see something different

20 SUV 10 SUV (B) PSMA FDG

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FDG+ PSMA- disease in liver (& bone)

20 SUV 10 SUV (B) (C) PSMA FDG PSMA/FDG

Can target with 177Lu- PSMA Cannot target

(most aggressive sites)

Thang SP et al Eur Urology Oncology 2018 #APCCC2019

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Disease heterogeneity: what does it mean?

(C) (D) (E) (F) (G) PSMA PSMA FDG FDG

Thang SP et al Eur Urology Oncology 2018

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PSMA- FDG+ PSMA+ FDG+ discordant

SUV 10

PSMA+ FDG+ concordant PSMA+ FDG-

SUV 20 SUV 10

Unsuitable Suitable

SUVmax 7 35 15 15 60 26 72 n/a

PSMA/FDG phenotypes

#APCCC2019

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PSMA- (or low expression) FDG+ PSMA+ FDG+ discordant

Unsuitable

SUVmax 7 35 15 15

What happened to the patients we didn’t treat?

16 patients excluded

low PSMA-expression (50%) discordant FDG+ disease (50%)

Median OS 2.5 months

(95% CI 1.7 – 5.0 months)

Thang SP et al Eur Urology Oncology 2018

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% survival + +

100% 75% 50% 25% 0%

3 6 9 12 15 18 21 24 27 30 months

  • A. OS

50 (0) 50 (0) 44 (0) 36 (0) 13 (0) 9 (1) 5 (3) 5 (3)

  • # at risk (censored)

29 (0) 20 (0) 19 (0)

Overall survival (n=50)

OS=13.3 months

(95% CI 10.5 - 18.7)

Hofman MS et al ASCO GU 2019 (updated May 2019)

% survival + p = 0.00017 0% 25% 100% 75% 50% 3 6 9 12 15 18 21 months Best PSA response > 50% ≥50%

PSA≥50%: 18.4 months (95% CI 13.8 – 23.8) PSA<50%: 8.7 months (95% CI 6.5 to 13.4)

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PSA≥50%: significantly longer overall survival

% survival + p = 0.00017 0% 25% 100% 75% 50% 3 6 9 12 15 18 21 months Best PSA response > 50% ≥50%

PSA≥50%: 18.4 months (95% CI 13.8 – 23.8) PSA<50%: 8.7 months (95% CI 6.5 to 13.4)

Hofman MS et al ASCO GU 2019 (updated May 2019)

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Prognostic markers with Lu-PSMA

+ + + + ++ +

0% 25% 50% 75% 100% 10 20 30 FDGvol

+ +

>= 207 ml < 207 ml

+ + ++ + + +

0% 25% 50% 75% 100% 10 20 30 PSMAmean

+ +

>= 10.55 < 10.55

+ + ++ + +

0% 25% 50% 75% 100% 10 20 30 LDH

+ +

>= 240.5 U/L < 240.5 U/L

+ + + ++ + +

0% 25% 50% 75% 100% 10 20 30 alkaline phosphatase

+ +

>= 126.5 U/L < 126.5 U/L

+ + + ++ +

0% 25% 50% 75% 100% 10 20 30 BSI

+ +

>= 5.37 % < 5.37 %

1 2 3 4 5

1: Whole-body FDG volume Cut-off : 207 ml Median OS: 6.1 vs 9.6 months (p < 0.001) 2: Whole-body PSMA SUVmean Cut-off : 10.3 Median OS: 9.8 vs 6.3 months (p = 0.002) 3: Lactate dehydrogenase Cut-off : 240.5 U/L Median OS: 6.9 vs 10.2 months (p = 0.03) 4: Alkaline phosphatase Cut-off : 126.5 U/L Median OS: 6.0 vs 9.7 months (p < 0.001) 5: EXINI Bone Scan Index (%) Cut-off : 5.37 % Median OS: 5.4 vs 8.3 months (p = 0.002)

months months months months months survival survival survival survival survival

FerdinandusJ, Hofman MS et al, (unpublished)

FDG volume PSMA intensity LDH ALP Bone scan index

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24hrs 96hrs 4hrs 3 x qSPECT/CT

Theranostics: we can quantify radiation dose (“dosimetry”)

Violet J … Hofman MS, JNM 2019

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2 x 106Bq/mL

24hrs 96hrs 4hrs CT-CT deformable image registration voxelised kinetics

(Bq/mL) mean voxel activity time (hours) 4 24 96

3 x qSPECT/CT

Dose in Gy (tumour and normal tissue) 50 Gy

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<50% ≥50% PSA Response

<10 Gy: 10 non-responders 1 responder

“Whole body” tumour dose correlates with PSA response @ 12 weeks

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TheraP Trial: 177Lu-PSMA-617 vs. cabazitaxel

Metastatic castration-resistant prostate cancer post docetaxel suitable for cabazitaxel PSMA + FDG PET/CT

▪ SUVmax > 20 at a site of disease ▪ Measurable sites SUVmax > 10 ▪ No discordant FDG+ PSMA-disease ▪ Centrally reviewed

177Lu-PSMA-617

▪ 8.5GBq  0.5GBq/cycle ▪ Up to 6 cycles cabazitaxel ▪ 20mg/m2 IV q3 weekly ▪ Up to 10 cycles SPECT/CT @ 24 hours

▪ Suspend Rx if exceptional response ▪ Recommence upon progression

N = 200; 11 sites (Australia) 1:1 randomisation stratified by:

  • disease burden (>20 sites vs ≤ 20 sites)
  • prior enzalutamide or abiraterone
  • site

Endpoints 1. PSA response 2. OS 3. rPFS / PSA PFS 4. QoL 5. AEs

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TheraP Trial: 177Lu-PSMA-617 vs. cabazitaxel

Metastatic castration-resistant prostate cancer post docetaxel suitable for cabazitaxel PSMA + FDG PET/CT

▪ SUVmax > 20 at a site of disease ▪ Measurable sites SUVmax > 10 ▪ No discordant FDG+ PSMA-disease ▪ Centrally reviewed

177Lu-PSMA-617

▪ 8.5GBq  0.5GBq/cycle ▪ Up to 6 cycles cabazitaxel ▪ 20mg/m2 IV q3 weekly ▪ Up to 10 cycles

20 40 60 80 100 120 140 160 180 200 Jan-18 May-18 Sep-18 Jan-19 May-19 Sep-19 Jan-20

Patients randomised

https://clinicaltrials.gov/ct2/show/NCT03392428 Australian Sponsor: ANZUP Study Chair: Prof Michael Hofman Co-ordinating Centre: NHMRC Clinical Trials Centre Collaborative Group Chair: Prof Ian Davis Funding: Prostate Cancer Foundation of Australia (PCFA), Endocyte, ANSTO, Movember

Senior Statistician: Dr Andrew Martin | CTC Clinical Lead: Prof Martin Stockler

1 more patient to recruit !

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VISION Trial: 177Lu-PSMA versus best supportive care

Primary Endpoint

  • Overall survival

Key Secondary Endpoints

  • Radiographic progression-free survival (rPFS)
  • RECIST response
  • Time to first symptomatic skeletal event (SSE)

Progressive mCRPC PSMA+ Previous taxane therapy and previous novel androgen axis therapy

Best supportive/ best standard

  • f care

177Lu-PSMA-617

(7.4GBq, 6 wkly X6 )

+

Best supportive/best standard of care

Best supportive/best standard of care

  • 9 Countries (NA and EU)
  • >750 patients recruited
  • 12-14 months FU min 15 month

2:1 randomiz izatio ion

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▪ Metastatic CRPC ▪ Progressed after enzalutamide, abiraterone

  • r apalutamide

PSMA + FDG PET/CT

Pembroluzimab 200mg

3 weekly

+

177Lu-PSMA-617

6 weekly, 4 cycles Day 4 ± 2 days 8.5 GBq, 0.5 GBq/cycle

PRINCE Trial

PSMA-lutetium Radionuclide therapy and ImmuNotherapy in prostate CancEr

clinicaltrials.gov: NCT03658447 PI: A/Prof Shahneen Sandhu

@UCSFImaging

NCT03805594

Dr Rahul Aggarwal Dr Tom Hope

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▪ Metastatic CRPC ▪ Progressed after 2nd generation AR-targeted agent ▪ Post taxane chemotherapy

PSMA + FDG PET/CT Olaparib day 2-15

3+3 dose escalation design 50mg to 300mg bd

(6 levels of increment)

+

177Lu-PSMA-617

6 weekly, 4 cycles 7.4 GBq

LuPARP Trial

Phase 1 trial of 177Lu-PSMA-617 therapy and Olaparib (PARPi)

clinicaltrials.gov: NCT03874884 PI: A/Prof Shahneen Sandhu

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#UpFrontPSMA: high-volume metastatic hormone naïve PC

\

ARM A (n = 70) Upfront Lu-PSMA x 2-3 + ADT followed by Docetaxel x 6 ARM B (n = 70) ADT + Docetaxel x 6 De novo High-Volume mHNPC

  • ≥ 4 bone mets with ≥ 1

extra-axial AND/OR

  • Visceral mets

Primary endpoint: undetectable PSA at 12 months

Statistical assumptions

  • P1 0.5, P2 0.25
  • 2-sided alpha=0.05, beta=0.8

PI: A/Prof Arun Azad

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#LuTectomy: 177Lu-PSMA prior to surgery

High-risk localised prostate cancer ± N1 High PSMA Expression

177Lu-PSMA

x 1-2 cycles

At 6-8 weeks:

  • Prostatectomy +

pelvic LN dissection

Primary endpoints:

  • Dosimetry

Key Secondary endpoints

  • Safety
  • PSMA PET Response

Hofman et al [unpublished)

Correlative samples

  • Tumour tissue
  • PBMCs
  • ctDNA, serum

GG9 post docet, abi, enza & cabazitaxel

45 Gy mean, 78 Gy max

PI: Prof Declan Murphy

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177Lu-PSMA shows promise: can it be used earlier?

LuPSMA LuPSMA

Chemotherapy

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177Lu-PSMA shows promise: can it be used earlier?

LuPSMA

Chemotherapy

+ combinations

+/- combined with other therapies?

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Molecular Imaging | Nuclear Medicine

▪ Rod Hicks (Director) ▪ Amir Iravani, Aravind Ravi Kumar, Grace Kong, Tim Akhurst, Ramin Alipour (Nuc Med “Dream T eam”) ▪ A/Prof Louise Emmett (St Vs, Sydney) ▪ Peter Eu (Radiopharmacist) ▪ Mark Scalzo (Lead T echnologist) ▪ Price Jackson (Medical Physicist)

Uro-oncology Multi-Disciplinary Team

▪ Scott Williams, John Violet, Shankar Siva (Rad Onc) ▪ Shahneen Sandhu, Arun Azad, Ben Tran (Med Onc) ▪ Declan Murphy, Nathan Lawrentschuk (Urology) ▪ Gail Risbringer (Laboratory Research)

Funding partners (alphabetical order)

▪ ANSTO (177Lu) ▪ Cancer Australia ▪ Endocyte / AAA (Novartis) ▪ Movember ▪ Peter MacCallum Foundation ▪ Prostate Cancer Foundation (PCF) ▪ Prostate Cancer Foundation of Australia (PCFA) ▪ Victorian Cancer Agency (VCA)

Collaborative partners

  • ANZUP Prof Ian Davis | Margaret McJannett
  • ARTnet A/Prof Ros Francis
  • BaCT
  • NHMRC CTC
  • PropPSMA & TheraP investigators

Thank-you #GoNuclear

DrMHofman