BLOOD BIOMARKERS · - Comprehensive tumor profile PCa heterogeneity - Non-invasive Biopsies not...

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BLOOD BIOMARKERS

ELENA CASTRO

Hospital V. de la VictoriaSpanish National Cancer Research Centre

ESMO Preceptorship on Prostate cancer.Lugano 17-18 October 2019

Disclosures

Participation in advisory boards: Astra-Zeneca, Astellas, Bayer, JanssenResearch funding: Astra Zeneca, Bayer, JanssenSpeaker fees: Astra Zeneca, Astellas, Bayer, Janssen, PfizerTravel, accomodation, expenses: Astellas, Astra-Zeneca, Bayer, Bristol-Myers,Janssen, Roche

BIOMARKER

A characteristic (clinical or molecular) that can be measured (objectively and reproducibly) to indicate a biologic condition (including normal or pathogenic processess) and also a response to a therapeutic intervention.

Bastos & Antonarakis, Expert Rev Mol Diagn, 2018

Docetaxel

Cabazitaxel

Abiraterone

Enzalutamide

Radium-223

Need for validated predictive biomarkers to guide therapeutic choices

BRCA1/2 alterations predict

response to PARP inhibitors

PROGNOSTIC Biomarkers

LABORATORYbiomarkers

CLINICALbiomarkers

IMAGINGbiomarkers

PATHOLOGIC /MOLECULARbiomarkers

- PSA (baseline and kinetics)

- LDH

- Hemoglobin

- Alkaline phosphatase

- Serum Albumin

- Neutrophil-lymphocyte

ratio (NLR)

- CTC count ≥ 5 vs ≤5- CTC count conversión

(<5) after 12 weeks

- Performance status

- Pain / use of opioids

- Sites of metastasis

- Extent of disease

- Histologic variants

- Gleason score

- Rb1, TP53, PTEN alterations

- AR-V7 detection

- AR copy number

- ctDNA fraction

- DDR genes alterations

Bastos & Antonarakis, Expert Rev Mol Diagn, 2018Terada et al, Ther Adv Med Oncol, 2017

Saad et a, Lancet Oncol, 2016

Alkaline Phosphatase Haemoglobin

ECOG Pain

PROSTATE SPECIFIC ANTIGEN (PSA)

• Definition of Castration Resistance

-Castrate serum levels of testosterone (testosterone <50ng/dl or <2nmol/l)

-Two consecutive rises of PSA, 1 week apart, resulting in a 50% increase over the nadir

-If MAB: Antiandrogen withdrawal for at least 4 weeks (flutamida) or 6 weeks (bicalutamide)

-Radiographic progression (RECIST 1.1 and PCWG3 criteria)

Monitoring PCa

PSA should be assessed by cycle (3 or 4 weeks)

PSA outcomes should be interpreted within the context of a drug’s mechanism of actionand the anticipated timing of a potential favorable/unfavorable effect on PSA should be considered

Recognize that a favourable effect on PSA may be delayed for ≥12 weeks, even for a cytotoxicdrug.

Ignore early rises (before 12 weeks) in determining PSA response Monitor PSA by cycle but plan to continue through early rises for a minimum of 12 weeks unless

other evidence of progression

PSA to monitor CRPC treatments

A. Time to PSA Progression B. Time to Radiographic Progression C. Time to Death

Outcome

Maximal Confirmed PSA Decline From Baseline at Month 3 in the Enzalutamide Arm (N = 795)a

No Decline/ Decline < 30%(n = 94/795)

≥ 30% Decline(n = 701/795)

≥ 50% Decline(n = 639/795)

≥ 90% Decline(n = 307/795)

Best objective soft-tissue response (CR + PR), % (95% CI)

12.0 (4.5-24.3) 70.6 (65.1-75.6)P < .001b

74.8 (69.2-79.9)P < .001b

89.7 (82.8-95.0)P < .001b

Median (95% CI) time to PSA progression, mo 3.7 (3.7-4.6) 13.8 (11.3-14.0) 13.9 (13.8-16.6) 22.5 (16.8-NYR)HR (95% CI) for time to PSA progression 1.0 (ref) 0.17 (0.13-0.22) 0.16 (0.12-0.20) 0.10 (0.08-0.14)

Median (95% CI) rPFS, mo 7.9 (3.7-NYR) NYR (13.8-NYR) NYR (13.8-NYR) NYR (13.8-NYR)HR (95% CI) for rPFS 1.0 (ref) 0.20 (0.13-0.31) 0.17 (0.11-0.27) 0.10 (0.05-0.19)

Median (95% CI) OS, mo 23.1 (17.8-28.0) 32.4 (31.5-NYR) NYR (31.5-NYR) NYR (NYR-NYR)HR (95% CI) for OS 1.0 (ref) 0.31 (0.22-0.42) 0.28 (0.20-0.39) 0.19 (0.12-0.28)

Armstrong, ESMO 2017

ORR = 70.6%*

423.5 25.9

45.3

8

47.1 48.9

44.4

68

27.8 23.79.4

18

1.6 1.5 0.92

0%10%20%30%40%50%60%70%80%90%

100%

No PSA Decline(n = 60)

PSA ≥ 30 Decline(n = 407)

PSA ≥ 50 Decline(n = 367)

PSA ≥ 90 Decline(n = 164)

Patie

nts,

%

Complete Response Partial Response Stable Disease Progressive Disease Not Evaluable

ORR = 89.7%*ORR = 74.8%*

PREVAIL: PSA decline associated with radiographic response

*P < .001 vs no PSA decline/PSA decline < 30% based on Fisher’s exact test. ClinicalTrials.gov identifier: NCT01212991. Abbreviations: ITT, intent to treat; ORR, objective response rate; PSA, prostate-specific antigen.

Armstrong, ESMO 2017

LATITUDE study: PSA response associated with better outcomesin mHSPC receiving ADT + AA + P or PBO

Matsubara N, et al. Ann Oncol 2018;29(Suppl 8):797PD.

Risk reduction AAP + ADT

Risk reduction PBO + ADT

50% PSA response ~56% (RR=0.44) ~41% (RR=0.59)

90% PSA response ~89% (RR=0.107) ~72% (RR=0.283)

Reduction in risk of death in PSA responders vs nonresponders

Time to PSA progression strongly correlated with rPFS (Kendall’s tau=0.9211) and OS (Kendall’s tau=0.666)

• Rising PSA is typically the first sign of tumour regrowth, preceding clinical and radiographic progression

Halabi et al , JCO, 2014

Halabi et al , JCO, 2014

Patient 1 Patient 2

ECOG 0 2

PSA 17.3 207

Disease site Lymphs only Visceral

Opioids use No Yes

LDH Normal >1ULN

Hemoglobin 14 10.8

Alkaline Phosphatase 119 247

- Comprehensive tumor profilePCa heterogeneity

- Non-invasiveBiopsies not always feasible

- Easily obtainedRepeatableMonitoring

CIRCULATING biomarkers

de Bono, Clin Cancer Res, 2008

CIRCULATING TUMOR CELLS

CTCs enumeration in mCRPC has been correlated with survival (prognostic biomarker)

CTC count ≥ 5 at baseline have worse survival

de Bono et al, Clin Cancer Res, 2008Olmos et al, Ann Oncol, 2009

CIRCULATING TUMOR CELLS

CTCs conversión associated with better outcomes

CTC conversión (from ≥ 5 to ≤ 5) after 12 weeks of therapy have better outcomes

CTC conversión (30% decrease) after 12 weeks of therapy have better outcomes

TOPARP-B

Bi-allelic BRCA (n=46)

Composite response rate 29/46 (63%)

Objective response rate 12/29 (41%)

PSA50 23/46 (50%)

CTC Conversion 18/38 (47%)

GALAHAD

CTCs to measure response in clinical trials

Mateo et al, NEJM, 2015; Mateo et al, ASCO 2019, Smith et al, ESMO 2019

Molecular characterization of CTCs

Attard et al, Cancer Res, 2009

AR splicing variants

Lallous et al, Int J Mol Sci, 2013

AR-V7 Adna test

Antonarakis et al. N Engl J Med 2014

Treatment1Baseline AR-V7+

Response

AR-V7 status PSA50 P- value rPFS P- value OS (95% CI) P value

Abiraterone(N=31) 19% (6/31)

+ 0% (0/6).004

2.3 mos<.001

10.6 mos (8.5–NR).002

– 68% (17/25) >6.3 mos >11.9 mos (11.9–NR)

Enzalutamide(N=31) 39% (12/31)

+ 0% (0/12).004

2.1 mos<.001

5.5 mos (3.9–NR).006

– 53% (10/19) 6.1 mos NR (NR–NR)

Adna-test

Epic test

Armstrong et al, JCO, 2019

Scher, JAMA Oncol, 2016

ARSi:PSA decline ≥50: 0% AR-V7+PSA decline <50%: 20%AR-V7+

No association between AR-V7 and response to taxanes

AR-V7 prevalence increases with disease progression

Response to taxanes independent of AR-V7

Annala et al, Cancer Discov, 2018

CIRCULATING TUMOR DNA (ctDNA)

Normal DNA

Tumour DNA

Annala et al, Cancer Discov, 2018

Annala et al, Cancer Discov, 2018

AR amplification and mutation do not preclude therapy response

Conteduca , Ann Oncol, 2017

Annala et al, Cancer Discov, 2018

AR gain associates with por OS and PFS

Annala et al, Cancer Discov, 2018Conteduca et al, Ann Oncol, 2017

Romanel et al, Sci Trans Med, 2015

Annala et al, Cancer Discov, 2018

Concordance of genome copy number between liquid and solid

biopsiesConcordance of mutation calls between solid and liquid biopsies

Wyatt et al, JNCI, 2017

Relationship between observed copy number and ctDNA fraction

Jayaram et al, Cancer Discov, 2018

A low ctDNA fraction limits the detection of less abundant subclonal aberrations and accurate estimation of copy-number changes, especially monoallelic mutations