Advanced Castrate Resistant Disease

8/10/2019 Advanced Castrate Resistant Disease

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Naomi B Haas, MDAssociate Professor of Medicine

Abramson Cancer Center

April 24, 2013


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Modulation of androgen and testosterone

New therapies for castrate resistantprostate cancer


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Intratumoral testosterone Androgen receptor (AR) mutations and splice

variants

Ligand modulation (things that influence theAR)

Targets in advance disease


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Castrate-treated with androgen deprivationtherapy

Non-castrate- not previously treated withandrogen deprivation therapy


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Rising PSA after surgery or radiation or both New metastatic disease and rising PSA :non-

castrate (not previously treated withandrogen deprivation therapy)

Metastatic castrate prostate cancer


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Orchiectomy LHRH (GHRH) (Luteinizing hormone releasing

hormone) agonists

Anti-androgens


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Anti-androgen LHRH

Pills Implants and shots

LHRH antagonist- degarelix


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Tiredness Metabolic syndrome- weight gain, high blood

pressure and high blood sugar Osteopenia-decreased bone density Secondary risks for heart attack, blood clot or

stroke Mood changes Loss of sex drive (libido) Hot flashes


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Prednisone 10 mg by mouth two times a daycan decrease PSA by more than 50% inapproximately 1/3 of patients with hormone-refractory progressive prostate cancer (Sartor Oet al, The Journal of Urology Vol161, Issue 1, January 1999,Page 360


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Scholz M et al. J Urol. 2005 Jun;173(6):1947-52.

Median and mean time to PSA progression was 6.7 and 14.5 months.

Median and mean survival time was 38.0 and 42.4 months, respectively.

Response time and survival were highly correlated (r = 0.799). A total of

34 (44%) men had a greater than 75% decrease in PSA. The median

survival times in men with more vs less than a 75% decrease were 60 vs24 months, respectively.

78 patients

0 1 to 3, >3 lesions bone scan

25, 35, and 18 patients


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Lyase inhibitors- get rid of intratumoral testosterone and

residual sources of testosterone/androgens

Abiraterone acetate and prednisone Tax 700

Toc 1 (dual lyase and AR inhibitor)

AR inhibitors- address mutations in the receptor, splice variants

MDV3100Aragon agent

Other AR ModulatorsHSP 90 inhibitorsHDAC inhibitors


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Prednisone Ketoconazole

Abiraterone


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AA (Zytiga) 1000mg qd + pred 5mg twice daily14 of 35 pts had decrease in PSA of >50%

Phase III trial completed post chemotherapy showed overallsurvival improvement of almost 5 months in a study of1000+ patients, leading to FDA approval


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Dizziness

Fatigue

Low or high blood pressure

Fluid retention

Elevation of liver enzymes Low potassium


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AR modulation


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Decline docetaxel

or are not suitable

for docetaxel

1:1 randomization

MDV3100

Something else

? patients

Coming soon


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Failed 1 or 2 prior

chemotherapies

(docetaxel)

2:1 randomization

MDV3100

Placebo

1170 patients

Improvement in overall survival of more than 5 months


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Asymptomatic

Castrate

metastatic disease

2:1 randomization

MDV3100

Placebo

850 patients

Closed to accrual in the US


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ARN-509 versus MDV3100


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ARN-509 versus MDV3100


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PK week Continuous Daily Dosing

Wk 1 2 3 4 5 9 13

Cycle 1 2 3

ARN-509

Single

Dose

Tumor

Evaluation

Q 12 wksDisease

Progression

DLT period for dose escalation

PSA

and CTC

Q 4 wks

ARN-509 dose escalation cohorts (n=3-6/cohort):

30, 60, 90, 120, 180, 240, 300, 390 and 480 mg

ARN-509 once daily until progression

PK D1-6

OptionalFDHT-PET

at

Baseline,

4 and 12

wks

Phase 1 Study Design


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-100

-75

-50

-25

0

25

50

75

100

%

PSAChangefromB

aseline

14 out of 29 patients (48.3%)

experienced 50% reduction in PSA at 12 weeks

30 mg

60 mg

90 mg

120 mg

180 mg

240 mg

300 mg

390 mg

480 mg

Dose

PSA Response Rates


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Baseline

4 Weeks

F-DHT-PET: Pharmacodynamic

MarkerOF AR INHIBITION IN RESPONSE TO ARN-509


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Metastatic

Post-Abiraterone

CRPCpatients

MetastaticTreatment-Nave

Non-Metastatic (M0)

(n = 93)

Primary Endpoint:12-week PSA response

Ongoing Phase 2 Trial

ASCO GU 2013


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Provenge Prostvac

CARs


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randomized (2:1) to receive 3 doses ofsipuleucel-T (n = 341) or placebo (n = 171)intravenously at 2-week intervals

median survival of 25.8 and 21.7 months

survival probability at 36 months of 32.1%and 23.0% in the sipuleucel-T and placeboarms

Kantoff GU ASCO 2010


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Harness antigens expressed uniquely by acancer (for example Prostate specificmembrane antigen, prostate specific stemcell antigen, F77, c-met ) and link to T cells

to turn on immunity against the antigen ongoing trials in leukemia, pancreatic cancer

Can be given IV or into the tumor


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Targets c-met and VEGFR2 both importanttargets in prostate cancer

c-met is overexpressed in bone metastasesas a later event in men on androgen

deprivation therapy

VEGF expressed in aggressive prostatecancer


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RDT trial in patients previously treated withdocetaxel showed 86% had response in bonescan; 65% had improvement in pain

Expanded prostate trial 64% (51/80 pts

evaluable) had a PR on bone scans, 24 pts(30%) SD at 100mg daily

other cohort treated at 39 mg daily resultspending

Two new phase III trials of XL184 coming


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Original Normalized CAD Annotated

Screening

Week 6

XL 1129-2408


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Original CAD AnnotatedNormalized

Screening

Week 6


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Original CAD AnnotatedNormalized

Screening

Week 6


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XL 1521-2565

Original Normalized

Screening

Week 6

CAD Annotated


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Adjuvant/

Neoadjuvant

Rising PSA Only Rising PSA

and

metastatic

disease

noncastrate)

Progression

after ADT

castrate)

Progression after

Docetaxel

TKIs +ADT ADT ADT Provenge Cabazetaxel

Docetaxel ECOG 2809 ketoconazole mitoxantrone andprednisone

abiraterone abiraterone

docetaxel enzalutamide

StrivePrevail

XL184?Radium chloride


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Biopsy with molecular profile Treatment with chemotherapy or targeted

agents or more hormonal therapy dependingon your molecular profile


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Hormone Sensit ive v. Hormone Refracto ry Prostate Cancer

Hormone Sensitive

Hormone Refractory

Biology

Clinical Trials

Open or Planned at

UPENN

1. High risk RT+ ADT+/- docetaxel

trial

2. everolimus + salvage XRT

3. Phase I Docetaxel/ cmet

inhibitor trial

4. CAR-T cells in advanced disease5. TKI258 plus INC280


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Combines VEGFR+ FGF inhibitor with a C-metinhibitor.

Phase I/II planned

Date post:	02-Jun-2018
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Advanced Castrate Resistant Disease

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