prostate cancer: what’s new? treatment options for advanced castrate resistant disease
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Naomi B Haas, MDAssociate Professor of Medicine
Abramson Cancer CenterApril 24, 2013
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 :non-
castrate (not previously treated with androgen deprivation therapy)
Metastatic castrate prostate cancer
Orchiectomy LHRH (GHRH) (Luteinizing hormone
releasing hormone) agonists Anti-androgens
Anti-androgen LHRH Pills 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 hormone-refractory 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.
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.
78 patients 0 1 to 3, >3 lesions bone scan25, 35, and 18 patients
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 variantsMDV3100Aragon agent
Other AR ModulatorsHSP 90 inhibitorsHDAC 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
Decline docetaxel or are not suitable for docetaxel
1:1 randomization MDV3100
Something else
? patients
Coming soon
Failed 1 or 2 prior chemotherapies (docetaxel)
2:1 randomization MDV3100
Placebo
1170 patients
Improvement in overall survival of more than 5 months
AsymptomaticCastrate metastatic disease
2:1 randomization MDV3100
Placebo
850 patients
Closed to accrual in the US
ARN-509 versus MDV3100
ARN-509 versus MDV3100
PK week Continuous Daily Dosing
Wk 1 2 3 4 5 9 13
Cycle 1 2 3
ARN-509Single Dose
Tumor EvaluationQ 12 wks
Disease Progression
DLT period for dose escalation
PSA and CTCQ 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
Optional FDHT-PET
at Baseline, 4 and 12
wks
Phase 1 Study Design
14 out of 29 patients (48.3%) experienced ≥ 50% reduction in PSA at 12 weeks
30 mg 60 mg 90 mg120 mg180 mg240 mg300 mg390 mg480 mg
Dose
PSA Response Rates
Baseline
4 Weeks
F-DHT-PET: Pharmacodynamic Marker
OF AR INHIBITION IN RESPONSE TO ARN-509
Ongoing Phase 2 Trial
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
Original Normalized CAD Annotated
Screening
Week 6
XL 1129-2408XL 1129-2408
Original CAD AnnotatedNormalized
Screening
Week 6
Original CAD AnnotatedNormalized
Screening
Week 6
XL 1521-2565XL 1521-2565
Original Normalized
Screening
Week 6
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 CabazetaxelDocetaxel ECOG 2809 ketoconazole mitoxantrone and
prednisone
abiraterone abiraterone
docetaxel enzalutamideStrivePrevail
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
Hormone Sensitive
Hormone Refractory
Biology
Clinical TrialsOpen or Planned at
UPENN
1. High risk RT+ ADT+/- docetaxel trial
2. everolimus + salvage XRT3. Phase I Docetaxel/ cmet
inhibitor trial4. CAR-T cells in advanced disease5. TKI258 plus INC280
Combines VEGFR+ FGF inhibitor with a C-met inhibitor.
Phase I/II planned
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