Prostate cancer what s new treatment options for advanced castrate resistant disease
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Prostate Cancer: What’s New? Treatment Options For Advanced Castrate Resistant Disease. Naomi B Haas, MD Associate Professor of Medicine Abramson Cancer Center. April 24, 2013. Objectives: to discuss the new modulation of androgen and the androgen receptor for prostate cancer.

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Prostate Cancer: What’s New? Treatment Options For Advanced Castrate Resistant Disease

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Prostate cancer what s new treatment options for advanced castrate resistant disease

Prostate Cancer: What’s New?Treatment Options For Advanced Castrate Resistant Disease

Naomi B Haas, MD

Associate Professor of Medicine

Abramson Cancer Center

April 24, 2013


Objectives to discuss the new modulation of androgen and the androgen receptor for prostate cancer

Objectives: to discuss the new modulation of androgen and the androgen receptor for prostate cancer

  • Modulation of androgen and testosterone

  • New therapies for castrate resistant prostate cancer


Overcoming resistance mechanisms in prostate cancer

Overcoming resistance mechanisms in prostate cancer:

  • Intratumoral testosterone

  • Androgen receptor (AR) mutations and splice variants

  • Ligand modulation (things that influence the AR)

  • Targets in advance disease


Semantics

Semantics

  • Castrate-treated with androgen deprivation therapy

  • Non-castrate- not previously treated with androgen deprivation therapy


Conventional categories

Conventional categories

  • Rising PSA after surgery or radiation or both

  • New metastatic disease and rising PSA :non- castrate (not previously treated with androgen deprivation therapy)

  • Metastatic castrate prostate cancer


Androgen deprivation therapy

Androgen deprivation Therapy

  • Orchiectomy

  • LHRH (GHRH) (Luteinizing hormone releasing hormone) agonists

  • Anti-androgens


Prostate cancer what s new treatment options for advanced castrate resistant disease

ADT

Anti-androgen LHRH

Pills Implants and shots

LHRH antagonist- degarelix


Side effects

Side Effects

  • 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


Other hormonal manipulations

Other Hormonal Manipulations

  • Prednisone 10 mg by mouth two times a day can decrease PSA by more than 50% in approximately 1/3 of patients with hormone-refractory progressive prostate cancer (Sartor O et al, The Journal of Urology Vol161, Issue 1, January 1999, Page 360


Other options ketoconazole prednisone or hydrocortisone

Other options: ketoconazole + prednisone or hydrocortisone

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

78 patients

0 1 to 3, >3 lesions bone scan

25, 35, and 18 patients

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 vs 24 months, respectively.


New hormonal manipulations

NEW Hormonal Manipulations!

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

    MDV3100

    Aragon agent

    Other AR Modulators

    HSP 90 inhibitors

    HDAC inhibitors


Other hormonal manipulations1

Other hormonal manipulations

  • Prednisone

  • Ketoconazole

  • Abiraterone


Prostate cancer what s new treatment options for advanced castrate resistant disease

Abiraterone acetate and prednisone in patients (Pts) with progressive metastatic castration resistant prostate cancer (CRPC) after failure of docetaxel-based chemotherapy.JClinOncol 26: 2008 (May 20 suppl; abstr 5019)

AA (Zytiga) 1000mg qd + pred 5mg twice daily

14 of 35 pts had decrease in PSA of >50%

Phase III trial completed post chemotherapy showed overall survival improvement of almost 5 months in a study of 1000+ patients, leading to FDA approval


Abiraterone side effects

Abiraterone side effects

  • Dizziness

  • Fatigue

  • Low or high blood pressure

  • Fluid retention

  • Elevation of liver enzymes

  • Low potassium


Mdv3100 enzalutamide xtandi

MDV3100/ Enzalutamide / Xtandi

AR modulation


Mdv 3100 phase ii trial

MDV 3100 Phase II trial

MDV3100

1:1 randomization

Decline docetaxel

or are not suitable

for docetaxel

Something else

? patients

Coming soon


Mdv 3100 phase iii affirm trial

MDV 3100 Phase III “AFFIRM” trial

MDV3100

2:1 randomization

Failed 1 or 2 prior

chemotherapies

(docetaxel)

Placebo

1170 patients

Improvement in overall survival of more than 5 months


Mdv 3100 phase iii prevail trial

MDV 3100 Phase III “PREVAIL” trial

MDV3100

2:1 randomization

Asymptomatic

Castrate

metastatic disease

Placebo

850 patients

Closed to accrual in the US


Prostate cancer what s new treatment options for advanced castrate resistant disease

ARN-509 versus MDV3100


Prostate cancer what s new treatment options for advanced castrate resistant disease

ARN-509 versus MDV3100


Prostate cancer what s new treatment options for advanced castrate resistant disease

Phase 1 Study Design

Optional FDHT-PET at Baseline, 4 and 12 wks

Tumor Evaluation

Q 12 wks

PSA and CTC

Q 4 wks

Disease Progression

ARN-509

Single Dose

ARN-509 once daily until progression

PK week Continuous Daily Dosing

PK D1-6

Wk 1 2 3 4 5 9 13

Cycle 1 2 3

DLT period for dose escalation

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

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


Prostate cancer what s new treatment options for advanced castrate resistant disease

PSA Response Rates

Dose

30 mg

60 mg

90 mg

120 mg

180 mg

240 mg

300 mg

390 mg

480 mg

  • 14 out of 29 patients (48.3%)

  • experienced ≥ 50% reduction in PSA at 12 weeks


Prostate cancer what s new treatment options for advanced castrate resistant disease

F-DHT-PET: Pharmacodynamic Marker

OF AR INHIBITION IN RESPONSE TO ARN-509

Baseline

4 Weeks


Prostate cancer what s new treatment options for advanced castrate resistant disease

Ongoing Phase 2 Trial

ASCO GU 2013


Immunotherapies

Immunotherapies

  • Provenge

  • Prostvac

  • CARs


Impact trial of sipuleucel t for metastatic castration resistant prostate cancer

IMPACT trial of sipuleucel-T for metastatic castration-resistant prostate cancer

  • randomized (2:1) to receive 3 doses of sipuleucel-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 placebo arms

  • Kantoff GU ASCO 2010


Cars c himeric a ntigen and t cell r eceptor carl june

CARs (ChimericAntigen and T cell Receptor)(Carl June)

  • Harness antigens expressed uniquely by a cancer (for example Prostate specific membrane antigen, prostate specific stem cell 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


Xl184 cabozantanib

XL184 (Cabozantanib)

  • Targets c-met and VEGFR2 both important targets in prostate cancer

  • c-met is overexpressed in bone metastases as a later event in men on androgen deprivation therapy

  • VEGF expressed in aggressive prostate cancer


Xl184 cabozantanib1

XL184 (Cabozantanib)

  • RDT trial in patients previously treated with docetaxel showed 86% had response in bone scan; 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 results pending

  • Two new phase III trials of XL184 coming


Xl 184 cases

XL 184 Cases


Prostate cancer what s new treatment options for advanced castrate resistant disease

XL 1129-2408

Screening

Week 6

Original

Normalized

CAD Annotated


Xl 1129 2426

XL 1129-2426

Screening

Week 6

Original

Normalized

CAD Annotated


Xl 1522 2459

XL 1522-2459

Screening

Week 6

Original

Normalized

CAD Annotated


Prostate cancer what s new treatment options for advanced castrate resistant disease

XL 1521-2565

Screening

Week 6

Original

Normalized

CAD Annotated


The landscape

The Landscape


The future

The future

  • Biopsy with molecular profile

  • Treatment with chemotherapy or targeted agents or more hormonal therapy depending on your molecular profile


Prostate cancer what s new treatment options for advanced castrate resistant disease

Hormone Sensitive

Hormone Refractory

Hormone Sensitive v. Hormone Refractory Prostate Cancer

Clinical Trials

Open or Planned at

UPENN

Biology

1. High risk RT+ ADT+/- docetaxel trial

2.everolimus + salvage XRT

3. Phase I Docetaxel/ cmet inhibitor trial

4. CAR-T cells in advanced disease

5. TKI258 plus INC280


Tki258 inc280

TKI258 + INC280

  • Combines VEGFR+ FGF inhibitor with a C-met inhibitor.

  • Phase I/II planned


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