Prostate Cancer: Diagnosis and Treatment

January 30, 2018 | Author: Anonymous | Category: Science, Health Science, Urology
Share Embed Donate


Short Description

Download Prostate Cancer: Diagnosis and Treatment...

Description

April 24, 2013

Naomi B Haas, MD Associate Professor of Medicine Abramson Cancer Center

 

Modulation of androgen and testosterone New therapies for castrate resistant prostate cancer

 





Intratumoral testosterone Androgen receptor (AR) mutations and splice variants Ligand modulation (things that influence the AR) Targets in advance disease





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

 



Rising PSA after surgery or radiation or both New metastatic disease and rising PSA :noncastrate (not previously treated with androgen deprivation therapy) Metastatic castrate prostate cancer

 



Orchiectomy LHRH (GHRH) (Luteinizing hormone releasing hormone) agonists Anti-androgens

Anti-androgen Pills

LHRH Implants and shots

LHRH antagonist- degarelix

    

 

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



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

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.

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

  

Prednisone Ketoconazole Abiraterone

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

     

Dizziness Fatigue Low or high blood pressure Fluid retention Elevation of liver enzymes Low potassium

AR modulation

1:1 randomization Decline docetaxel or are not suitable for docetaxel

? patients

Coming soon

MDV3100

Something else

2:1 randomization Failed 1 or 2 prior chemotherapies (docetaxel)

MDV3100

Placebo

1170 patients

Improvement in overall survival of more than 5 months

2:1 randomization Asymptomatic Castrate metastatic disease

850 patients

Closed to accrual in the US

MDV3100

Placebo

ARN-509 versus MDV3100

ARN-509 versus MDV3100

Phase 1 Study Design ARN-509 Single Dose

Optional FDHT-PET at Baseline, 4 and 12 wks

PSA and CTC Q 4 wks

Tumor Evaluation Q 12 wks

Disease Progression

ARN-509 once daily until progression

PK week

Continuous Daily Dosing

PK D1-6

Wk 1

Cycle

2

3

4

5

1

9

2

13

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

PSA Response Rates 100

Dose 30 mg 60 mg 90 mg 120 mg 180 mg 240 mg 300 mg 390 mg 480 mg

% PSA Change from Baseline

75 50 25 0

-25 -50 -75

-100

14 out of 29 patients (48.3%) experienced ≥ 50% reduction in PSA at 12 weeks

F-DHT-PET: Pharmacodynamic Marker OF AR INHIBITION IN RESPONSE TO ARN-509

Baseline

4 Weeks

Ongoing Phase 2 Trial Non-Metastatic (M0) CRPC patients (n = 93)

Metastatic Treatment-Naïve Metastatic Post-Abiraterone

Primary Endpoint: 12-week PSA response ASCO GU 2013

  

Provenge Prostvac CARs



 



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



 

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







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









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 1129-2408

Screening

Week 6

Original

Normalized

CAD Annotated

Screening

Week 6

Original

Normalized

CAD Annotated

Screening

Week 6

Original

Normalized

CAD Annotated

XL 1521-2565

Screening

Week 6

Original

Normalized

CAD Annotated

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 and prednisone

abiraterone

abiraterone

docetaxel

enzalutamide

Strive Prevail

XL184? Radium chloride

 

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

Hormone Sensitive v. Hormone Refractory Prostate Cancer

Clinical Trials Open or Planned at UPENN Biology Hormone Sensitive

Hormone Refractory

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





Combines VEGFR+ FGF inhibitor with a C-met inhibitor. Phase I/II planned

View more...

Comments

Copyright � 2017 NANOPDF Inc.
SUPPORT NANOPDF