Biomarkers in Prostate Cancer, part IIBiomarkers in Prostate Cancer, part IIProstate Cancer SymposiumProstate Cancer Symposium

September 17, 2011September 17, 2011

Clara Hwang, MDClara Hwang, MD

Internal MedicineInternal Medicine

Hematology/OncologyHematology/Oncology

Biomarkers – the holy grail of Biomarkers – the holy grail of personalized medicine?personalized medicine?

• Advances in technology (genomics, proteomics) Advances in technology (genomics, proteomics) have offered the promise of personalized have offered the promise of personalized medicine, where therapies and medical decision medicine, where therapies and medical decision making can be finely tailored to patients.making can be finely tailored to patients.

• Potential benefits include improving clinical Potential benefits include improving clinical efficacy and decreasing toxicity by better efficacy and decreasing toxicity by better treatment selection and patient selection.treatment selection and patient selection.

Phases of biomarker developmentPhases of biomarker development

• Discovery – ~Phase IDiscovery – ~Phase I• Identify relationship between molecular marker and clinical Identify relationship between molecular marker and clinical

outcome; ideally identify causal relationshipoutcome; ideally identify causal relationship

• Analytic Validation – ~Phase IIAnalytic Validation – ~Phase II• Develop lab SOP/QC, reliability in clinical samplesDevelop lab SOP/QC, reliability in clinical samples• Selectivity, sensitivity, CR, precision, accuracy Selectivity, sensitivity, CR, precision, accuracy

• Clinical Qualification – ~Phase IIIClinical Qualification – ~Phase III• Confirm correlation with clinical outcomesConfirm correlation with clinical outcomes

• Clinical implementation - ~Phase IVClinical implementation - ~Phase IV

Clinical utility of biomarkers Clinical utility of biomarkers in prostate cancer in prostate cancer

Clinical scenario Example

Detection PSA for early diagnosis

Prognosis Gleason score

Prediction ER positivity and hormone Rx;none exist for prostate cancer

Pharmacodynamic Testosterone for GnRH agonist

Clinical surrogate PSA decline as tumor marker

Prostate cancer clinical statesProstate cancer clinical statesand treatment decisionsand treatment decisions

Localized disease

Metastatic disease

Should I start treatment? (Prognostic biomarker)

Which treatment should I use? (Predictive biomarker)

Is my treatment working? (Pharmacodynamic biomarker)

Is my treatment helping the patient? (Surrogate biomarker)

Current landscape of treatments for castrate-Current landscape of treatments for castrate-resistant metastatic prostate cancerresistant metastatic prostate cancer

• Minimally symptomatic – sipuleucel-TMinimally symptomatic – sipuleucel-T• 11stst line – docetaxel line – docetaxel• 22ndnd line – line –

• Abiraterone Abiraterone • Cabazitaxel Cabazitaxel

• 33rdrd line – mitoxantrone line – mitoxantrone

Biomarkers to assess response to Biomarkers to assess response to systemic therapysystemic therapy

• Limitations of systemic therapy – all Limitations of systemic therapy – all patients will ultimately progresspatients will ultimately progress

• Some patients will not have an initial Some patients will not have an initial response to therapyresponse to therapy

• Are there predictive or surrogate Are there predictive or surrogate biomarkers to guide treatment decisions?biomarkers to guide treatment decisions?

Response markers in prostate cancerResponse markers in prostate cancer

• In current clinical useIn current clinical use• PSAPSA• Pain Pain • Bone scanBone scan• CT scan/ MRI scan (RECIST)CT scan/ MRI scan (RECIST)

• ExperimentalExperimental• Circulating tumor cellsCirculating tumor cells

The difficulty of assessing response to The difficulty of assessing response to therapy in mCRPCtherapy in mCRPC

““PCWG2 advises that, in the absence of PCWG2 advises that, in the absence of clinically compelling indicators of disease clinically compelling indicators of disease progression, early changes (within 12 progression, early changes (within 12 weeks) in indicators such as serum PSA, weeks) in indicators such as serum PSA, patient-reported pain, and radionuclide patient-reported pain, and radionuclide bone scan be ignored.”bone scan be ignored.”

Scher et al JCO 2008 v26(7) p 1148

Clinical examples of using PSA as Clinical examples of using PSA as biomarker for treatment responsebiomarker for treatment response

• PSA responses from PSA responses from three patients started on three patients started on chemotherapy with CRPCchemotherapy with CRPC

• On occasion, PSA will On occasion, PSA will rise prior to falling (PSA rise prior to falling (PSA flare response)flare response)

PSA response as surrogate markerPSA response as surrogate marker

• Retrospective analysis of patients on Ph III Retrospective analysis of patients on Ph III comparision of D+E vs M+P (S9916)comparision of D+E vs M+P (S9916)

• 3 month 30% PSA decline defined to have 3 month 30% PSA decline defined to have occurred if lowest PSA within first three occurred if lowest PSA within first three months <=50% of baseline valuemonths <=50% of baseline value

• By this definition – occurred in 76% in D+E By this definition – occurred in 76% in D+E arm vs 40% in M+Parm vs 40% in M+P

Petrylak 2006 JNCI 98:516

PSA decline as surrogate marker in PSA decline as surrogate marker in S9916S9916

Original figure of MP vs. DE compared to OS curve of patients with PSA decrease >=30% in 3 mo vs < 30%

Petrylak 2006 JNCI 98:516

Circulating tumor cells (CTC)Circulating tumor cells (CTC)

• In patients with solid tumors, circulating In patients with solid tumors, circulating tumor cells can be detected in circulationtumor cells can be detected in circulation

• Rare (1 in 10Rare (1 in 1099 nucleated cells) nucleated cells)

• Provide a source of tumor cells for Provide a source of tumor cells for molecular profilingmolecular profiling

• For Cellsearch assay, cutoff for favorable For Cellsearch assay, cutoff for favorable vs unfavorable is 5 CTC per 7.5 mL bloodvs unfavorable is 5 CTC per 7.5 mL blood

CTC detection with CellSearchCTC detection with CellSearch

Only FDA approved, analytically validated CTC assay

Baseline CTC is prognostic in mCRPC Baseline CTC is prognostic in mCRPC patients treated with cytotoxic therapypatients treated with cytotoxic therapy

de Bono J S et al. Clin Cancer Res 2008;14:6302-6309

Conversion of CTC as predictor of Conversion of CTC as predictor of overall survival overall survival

de Bono J S et al. Clin Cancer Res 2008;14:6302-6309

CTC enumeration vs PSA decline as CTC enumeration vs PSA decline as predictor of overall survivalpredictor of overall survival

Clinical utility of biomarkers Clinical utility of biomarkers in prostate cancer, revisitedin prostate cancer, revisited

Clinical scenario Example

Detection PSA for early diagnosis

Prognosis Gleason score

Prediction ER positivity and hormone Rx;none exist for prostate cancer

Pharmacodynamic Testosterone for GnRH agonist

Clinical surrogate PSA decline as tumor marker

Markers that correlate with docetaxel-Markers that correlate with docetaxel-sensitivitysensitivity

underexpressed in sensitive cell lines overexpressed in sensitive cell lines

Effect of SKP2 knockdown on docetaxel response

docetaxel concentration (log scale)

1 10 100

Ce

ll v

iab

ilit

y,

% b

as

eli

ne

40

60

80

100

Actin

SKP2

si-S

KP2si

-Non

Targ

et

0.0

0.2

0.4

0.6

0.8

1.0

LNCAP

Rel

ativ

e Q

uan

tita

tio

n

si-SKP2

si-nontarget

Causal relationship between SKP2 and Causal relationship between SKP2 and docetaxel responsedocetaxel response

ConclusionsConclusions

• PSA decline may be used as a surrogate PSA decline may be used as a surrogate marker for response (after 12 weeks)marker for response (after 12 weeks)

• Baseline levels of CTC are prognostic for Baseline levels of CTC are prognostic for OSOS

• Conversion of CTC correlates with OS but Conversion of CTC correlates with OS but have not yet been qualified for individual have not yet been qualified for individual patient usepatient use

• Further studies are needed to identify and Further studies are needed to identify and validate predictive markersvalidate predictive markers