10/17/2014 1 Optimal Management of Castration Resistant Prostate Cancer (CRPC) in 2014 15th Annual Advances in Oncology October 10-11, 2014 Primo N. Lara, Jr., MD Professor of Medicine UC Davis School of Medicine Disclosures Consultant: Janssen Pharmaceuticals, Clovis Oncology, US Diagnostic Services, Astex Therapeutics, Exelixis, Immunogen, Pfizer, Teva, Medivation, Halozyme, Novartis Grant/Research Support: Millennium, Polaris, Oncogenex, GlaxoSmithKline, Genentech, Aragon Pharmaceuticals, Janssen Biotech, Inc. The presentation (does not include) discussion of the use of product(s) for which they are not labeled (e.g., off label use) is still investigational. Acknowledgement Daniel Petrylak MD (Yale University) for allowing me to “borrow” some of his slides! CRPC therapy by state: 2010 Zoledronic acid with CRPC (metastatic disease) Metastatic, minimally symptomatic CRPC Symptomatic or poor- prognosis CRPC Progression after docetaxel chemotherapy Secondary hormonal Rx Docetaxel Mitoxantrone Best supportive care not known 3 months not known Survival benefit 2010 CRPC therapy by state: 2014 Abiraterone or Cabazitaxel acetate Metastatic, minimally symptomatic CRPC Symptomatic or poor- prognosis CRPC Progression after docetaxel chemotherapy Secondary hormonal Rx Docetaxel not known 3 months not known Sipuleucel-T Docetaxel 4 months 3 months 4 months 2.5 months Denosumab or Zoledronic acid (bone metastatic disease) Survival benefit Survival benefit Mitoxantrone Best supportive care 2010 2014 Enzalutamide – 4.8 months Rad223 – 3.1 months Enzalutamide – 2.2 months Abiraterone – 5.2 months Rad223 – 4.6 months Development of CRPC ALTERN. SPLICING ABERRANT MODIFICATION •GF, cytokines •Src Sumo AC P COFACTOR PERTURBATION •CoAct gain •CoR loss/dismissal CoACT INTRACRINE ANDROGEN SYNTHESIS T MUTATION •gain of function AR selective pressure Hormone Therapy adaptation CRPC RESTORED AR ACTIVITY (rising PSA) RECURRENT TUMOR DEVELOPMENT >30% CRPC AR DEREGULATION •amplification •overexpression Penning and Knudsen. Trends Endocrinol Metab. 2010;21(5):315-24. Classes of Agents in CRPC • Immunotherapeutic – Sipuleucel T • Androgen-receptor targeted – Enzalutamide, Abiraterone , ?Docetaxel • Cytotoxic – Docetaxel, Cabazitaxel • Radioisotope – Radium 223
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10/17/2014
1
Optimal Management of
Castration Resistant Prostate Cancer (CRPC) in 2014
¥ CRPC patients who have been treated with docetaxel chemotherapy (and abiraterone pre-chemotherapy is
acceptable) will have a radiographic metastatic soft tissue or bone biopsy, which is mandatory at screening and
optional at progression. Abiraterone may have only been given pre-chemotherapy.
Androgen Receptor Splice Variants
Some variants still constitutively active as transcription factor despite lack of LBD
AR Splice Variant Mediated Resistance
Nelson, NEJM 2014
Antoranakis, NEJM 2014
10/17/2014
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6 injections at 4-week intervals
Radium-223 dichloride (50 kBq/kg) +
best standard of care†
Placebo (saline) + best standard of care†
•Total ALP: < 220 U/L vs. ≥ 220 U/L •Bisphosphonate use: Yes vs. No •Prior docetaxel: Yes vs. No
•Confirmed Symptomatic CRPC
•≥2 bone metastases
•No known visceral metastases
•Post-docetaxel or unfit for docetaxel*
Radium 223 Phase III Study Design1
Reference: 1. Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.
*Unfit for docetaxel includes patients who were ineligible for docetaxel, refused docetaxel, or lived where docetaxel was unavailable †Best standard of care defined as a routine standard of care at each center, eg. local external beam radiotherapy, corticosteroids, anti-androgens, estrogens (e.g., stilbestrol), estramustine, or ketaconazole
PATIENTS STRATIFICATION
R
A
N
D
O
M
I
Z
E 2:1
N=921
TREATMENT PHASE
>100 centers in 19 countries Planned follow-up is 3 years