immunotherapy and other new drug targets -...
TRANSCRIPT
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IMMUNOTHERAPY AND OTHER
NEW DRUG TARGETS
A/Prof. Arun Azad MBBS PhD FRACP
Medical Oncologist – Monash Health, Melbourne, Australia
Translational Researcher - Monash University, Melbourne, Australia
Chair - Translational Research Committee, ANZUP Clinical Trials
Group
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Disclosures
Research Support/P.I. Astellas
Employee N/A
Consultant Astellas, Janssen, Novartis
Major Stockholder N/A
Speakers Bureau Janssen
Honoraria Astellas, Janssen, Novartis, Tolmar, Amgen
Scientific Advisory Board Astellas, Novartis, Sanofi, Astra-Zeneca, Tolmar
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Shifting Treatment Landscape for CRPC: Positive Phase 3 Trials
Mitoxantrone
Zoledronic Acid
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Docetaxel
Enzalutamide
Abiraterone acetate
Cabazitaxel
Denosumab
Radium-223
Sipuleucel-T
Symptom benefit
Skeletal Related Event (SRE) benefit
Overall survival benefit ± symptom/SRE benefit
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1999
Median survival from time of first
mitoxantrone chemotherapy = 12.3 months
2012
Median survival from time of first
docetaxel chemotherapy = 32.6 months
Kantoff, JCO, 1999; Chi, J Clin Oncol 30, 2012 (suppl 5; abstr 15)
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But…...
� Metastatic CRPC remains incurable
� Most men with metastatic CRPC will die from their disease
� Existing drugs work well in many cases but adaptive resistance is
essentially inevitable
� So, we urgently need new drugs to emerge into the clinic
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Emerging drug targets in CRPC
� PARP
� PI3K/Akt
� AR (non-ligand binding domain)
� Prostate-specific membrane antigen (PSMA)
� Immune checkpoints
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PARP inhibitors
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Synthetic lethality
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BRCA -/- cells are exquisitely sensitive to PARP inhibition
Farmer et al, Nature 2005 Bryant et al, Nature 2005
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DNA repair defects in metastatic CRPC
22.7% DNA
repair defects
(34/150)
12.7% BRCA2
altered (19/150)
including 5.3%
germline (8/150)
Robinson et al, Cell 2015
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TOPARP trial
49 evaluable pts
-RR 33%
16/49 pts had DNA
repair defect
-RR 88%
Mateo et al, NEJM 2015
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TOPARP trial
Mateo et al, NEJM 2015
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Targeting PARP in mCRPC: ongoing/upcoming trials
� PROfound trial opening Q12017
– Phase III olaparib
� Multiple single-agent Ph II studies open/near opening
– Medivation, Janssen, Clovus
� Combination studies with PARPi + AR-targeted agents
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PI3K/Akt
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PI3K-AKT signalling cascade
Controls key cellular
processes including
growth, survival,
proliferation &
angiogenesis
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PI3K-AKT signalling cascade
Robinson et al, Cell 2015
PI3K pathway
alterations in
73/150 (49%)
Toren et al, Eur Urol 2015
Reciprocal regulation between AR & PI3K
Strong pre-clinical rationale for co-targeting
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Background<br />A.MARTIN Phase II trial design
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Results<br />Radiographic progression-free survivala
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PTEN loss: a key predictive biomarker
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Targeting PI3K/Akt in mCRPC: ongoing/upcoming trials
� Ph III study Abiraterone +/- Ipatasertib in PTEN loss mCRPC
� Ph II study Enzalutamide +/- AZD5363
� Ph I study Enzalutamide + GSK2636771
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AR (non-ligand binding domain)
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EPI-001: N-terminal domain inhibitor
M. Sadar, Cancer Res, 71:1208, 2011
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EPI-001: N-terminal domain inhibitor
RJ Andersen…M Sadar, Cancer Cell 17:535, 2010
EPI-001 identified by
screening a library of
marine sponge extracts
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EPI-001: Targeting ARV+ PCa
EPI-001 efficacious
against CRPC with FL-AR
and ARVs
Myung et al, JCI 2013
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Prostate-specific membrane antigen
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PSMA
� Type 2 transmembrane protein
over-expressed on prostate
adenocarcinoma cells
– PSMA PET widely adopted in
Australia as superior sensitivity to
CT + WBBS
� Also can be expressed on:
– Tumour neovasculature (including
colon, breast and renal cancer and
subtypes of bladder cancer)
– Any new blood vessels
– Astrocytes
Maurer et al, Nat Rev Urol 2016
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Lu-PSMA: A new theranostic?
76-y-old patient after external-beam radiation therapy to bone metastases and hormone therapy. Richard P. Baum et al. J Nucl Med 2016;57:1006-1013
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Lu-PSMA: A new theranostic?
PSA, SUVmax, and response assessment. Richard P. Baum et al. J Nucl Med 2016;57:1006-1013
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Immune checkpoints
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Immunotherapy: The new frontier?
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Targeting CTLA-4 in CRPC
Overall survival Progression-free survival
Kwon et al, Lancet Oncol 2014
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Targeting PD-1 in CRPC
0/17 (0%) RR in
mCRPC patients
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PCa: Phase II Pembro / Enza J Graff
PDL1 expression increases on
resistance to enzalutamide
Pembrolizumab = PD1-i
200mg iv q3wk x4 doses
Med time on Enza 52wk
Prior response on Enza: 23 pts
Hansen et al
• Ph 1b pembro
• CRPC cohort (n=23)
• RR 13%, SD 39%
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I/O in mCRPC: Ongoing/upcoming trials
� Keynote-199: Pembro
� Keynote-265: Pembro + multiple combination arms
� Multiple Ph I/II I/O studies with a mCRPC cohort
Abi or Enza Abi or Enza resistant mCRPC (n=25)
Avelumab (PD-L1) + SABR
(up to 3 mets)
Primary endpoint: rPFS
at 6 months
Phase II IIS opening early
2017 (Arun Azad, study
chair)
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Summary
� Rapid explosion in systemic therapies for prostate cancer
� Most men with advanced disease still die from their cancer
� Improving outcomes requires new drugs/targets
– PARP
– PI3K/Akt
– AR non-LBD
– PSMA (theranostic)
– I/O
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THANK YOU