Prostate Cancer: Diagnosis and Treatment
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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
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