PROSTATE CANCER CIRCULATING BIOMARKER CONSENSUS STATEMENT QUESTIONS

In your opinion, is cell-free DNA testing ready for use in daily routine clinical practice? Yes No but current data supports testing in prospective trials No and further clinical studies are required prior to prospective, clinical validation studies Abstain/Unqualified to answer Detailed voting results Option 1 1 Option 2 10 Option 3 6 Option 4 N 17

Detailed voting results In your opinion, is quantitative analysis of cell-free DNA concentration ready for use in daily routine clinical practice? Yes No but current data supports testing in prospective trials No and further clinical studies are required prior to prospective, clinical validation studies Abstain/Unqualified to answer Detailed voting results Option 1 Option 2 7 Option 3 11 Option 4 N 18

In your opinion, is tissue based germline and/or somatic analysis of gene panels ready for use in daily routine clinical practice? Yes No but current data supports testing in prospective trials. No and further clinical studies are required prior to prospective, clinical validation studies. Abstain/Unqualified to answer Detailed voting results Option 1 7 Option 2 Option 3 2 Option 4 1 N 17

Based on current knowledge what is the most appropriate clinical situation for cell-free circulating DNA testing if the tests were readily available? Before starting treatment for metastatic prostate cancer Before starting first-line mCRPC treatment Before starting ≥second line mCRPC treatment All of the above No appropriate clinical situation currently Abstain/Unqualified to answer Detailed voting results Option 1 1 Option 2 Option 3 6 Option 4 5 Option 5 3 Option 6 N 17

Based on the current knowledge what is the most appropriate clinical situation for CTC testing if the tests were readily available? Before starting treatment for metastatic prostate cancer Before starting first-line mCRPC treatment Before starting ≥second line mCRPC treatment All of the above No appropriate clinical situation currently Abstain/Unqualified to answer Detailed voting results Option 1 Option 2 5 Option 3 3 Option 4 7 Option 5 Option 6 N 18

In your opinion, is genomic analyses of cell-free, gene panel DNA testing ready for use in daily routine clinical practice? Yes No but current data supports testing in prospective trials. No and further clinical studies are required prior to prospective, clinical validation studies. Abstain/Unqualified to answer Detailed voting results Option 1 1 Option 2 13 Option 3 4 Option 4 N 18

In your opinion, is CTC testing ready for use in daily routine clinical practice? Yes No but current data supports testing in prospective trials. No and further clinical studies are required prior to prospective, clinical validation studies. Abstain/Unqualified to answer Detailed voting results Option 1 6 Option 2 11 Option 3 1 Option 4 N 18

In your opinion, is CellSearchTM CTC count estimation ready for use in daily routine clinical practice? Yes No but current data supports testing in prospective trials. No and further clinical studies are required prior to prospective, clinical validation studies. Abstain/Unqualified to answer Detailed voting results Option 1 12 Option 2 4 Option 3 2 Option 4 N 18

In your opinion, is genomic analysis of CTCs ready for use in daily routine clinical practice? Yes No but current data supports testing in prospective trials. No and further clinical studies are required prior to prospective, clinical validation studies. Abstain/Unqualified to answer Detailed voting results Option 1 Option 2 11 Option 3 7 Option 4 N 18

In your opinion, is AR-V7 testing ready for use in daily routine clinical practice? Yes No but current data supports testing in prospective trials. No and further clinical studies are required prior to prospective, clinical validation studies. Abstain/Unqualified to answer Detailed voting results Option 1 1 Option 2 13 Option 3 4 Option 4 N 18

Which AR-V7 test should be employed in daily routine clinical practice if only one test was funded? EPIC AR V7 CTC protein assay Hopkins/Qiagen AR-V7 RT-PCR CTC assay Custom RT-PCR based CTC assay Custom protein-based CTC assay Any/either of these tests No appropriate assay currently Abstain/Unqualified to answer Detailed voting results Option 1 4 Option 2 1 Option 3 Option 4 Option 5 Option 6 6 Option 7 N 17

In your opinion, is AR copy gain/mutation in cell-free DNA testing ready for use in daily routine clinical practice? Yes No but current data supports testing in prospective trials. No and further clinical studies are required prior to prospective, clinical validation studies. Abstain/Unqualified to answer Detailed voting results Option 1 Option 2 15 Option 3 3 Option 4 N 18

Based on the current knowledge what is the most appropriate clinical situation for AR- V7/AR copy gain/AR mutation testing if the test were readily available? Before starting treatment for metastatic prostate cancer Before starting first-line mCRPC treatment Before starting ≥second line mCRPC treatment All of the above No appropriate clinical situation currently Abstain/Unqualified to answer Detailed voting results Option 1 Option 2 3 Option 3 5 Option 4 Option 5 4 Option 6 1 N 18

In your opinion, are cfDNA assays likely to impact patient care by 2020? Yes Likely Possibly No Abstain/Unqualified to answer Detailed voting results Option 1 12 Option 2 3 Option 3 2 Option 4 1 Option 5 N 18

In your opinion, are CTC assays likely to impact patient care by 2020? Yes Likely Possibly No Abstain/Unqualified to answer Detailed voting results Option 1 6 Option 2 Option 3 5 Option 4 1 Option 5 N 18

In your opinion and if you had a choice is a biopsy assay preferable to a blood-based assay when both are feasible? Yes No Abstain/Unqualified to answer Detailed voting results Option 1 5 Option 2 12 Option 3 1 N 18

17.In your opinion what is the clinical need for: Circulating biomarkers for DIAGNOSTIC purposes Very high (high clinical need, development urgently needed) High (relevant clinical need) Low (not key priority for this purpose) Abstain/Unqualified to answer Detailed voting results Option 1 8 Option 2 5 Option 3 Option 4 N 18

18.For which clinical situation is the development of circulating biomarkers for DIAGNOSTIC use most relevant? Population-based screening for prostate cancer Localised/locally-advanced prostate cancer Recurrence after radical treatment Metastatic prostate cancer Abstain/Unqualified to answer Detailed voting results Option 1 9 Option 2 2 Option 3 1 Option 4 6 Option 5 N 18

In your opinion what is the clinical need for: PROGNOSTIC circulating biomarkers Very high (high clinical need, development urgently needed) High (relevant clinical need) Low (not key priority for this purpose) Abstain/Unqualified to answer Detailed voting results Option 1 3 Option 2 5 Option 3 10 Option 4 N 18

For which clinical situation is the development of PROGNOSTIC circulating biomarkers most relevant? Population-based screening for prostate cancer Localised/locally-advanced prostate cancer Recurrence after radical treatment Metastatic prostate cancer Abstain/Unqualified to answer Detailed voting results Option 1 Option 2 10 Option 3 3 Option 4 4 Option 5 N 17

In your opinion what is the clinical need for: PREDICTIVE circulating biomarkers Very high (high clinical need, development urgently needed) High (relevant clinical need) Low (not key priority for this purpose) Abstain/Unqualified to answer Detailed voting results Option 1 17 Option 2 1 Option 3 Option 4 N 18

For which clinical situation is the development of PREDICTIVE circulating biomarkers most relevant? Population-based screening for prostate cancer Localised/locally-advanced prostate cancer Recurrence after radical treatment Metastatic prostate cancer Abstain/Unqualified to answer Detailed voting results Option 1 Option 2 2 Option 3 Option 4 16 Option 5 N 18

Which systemic therapy is in GREATEST need of a PREDICTIVE circulating biomarker in men with mCRPC? Abiraterone or enzalutamide Taxane chemotherapy Radium-223 PARP inhibition or platinum based chemotherapy Immunotherapy All of the above None of the above Abstain/unqualified to answer Detailed voting results Option 1 2 Option 2 Option 3 Option 4 Option 5 5 Option 6 9 Option 7 Option 8 N 18

Which systemic therapy has the LEAST need of a PREDICTIVE circulating biomarker in men with mCRPC? Abiraterone or enzalutamide Taxane chemotherapy Radium-223 PARP inhibition or platinum based chemotherapy Immunotherapy All of the above None of the above Abstain/unqualified to answer Detailed voting results Option 1 1 Option 2 3 Option 3 6 Option 4 Option 5 Option 6 Option 7 7 Option 8 N 17

A circulating biomarker of DNA homologous repair deficiency would have the greatest clinical utility in which setting? At diagnosis of localized disease At diagnosis of metastatic disease At diagnosis of mCRPC mCRPC following progression of abiraterone or enzalutamide mCRPC following progression on all proven therapies Detailed voting results Option 1 1 Option 2 8 Option 3 4 Option 4 Option 5 3 N 17

In your opinion what is the clinical need for: Circulating RESPONSE biomarkers Very high (high clinical need, development urgently needed) High (relevant clinical need) Low (not key priority for this purpose) Abstain/Unqualified to answer Detailed voting results Option 1 13 Option 2 3 Option 3 2 Option 4 N 18

For which clinical situation is the development of circulating RESPONSE biomarkers most relevant? Population-based screening for prostate cancer Localised/locally-advanced prostate cancer Recurrence after radical treatment Metastatic prostate cancer Abstain/Unqualified to answer Detailed voting results Option 1 Option 2 Option 3 Option 4 17 Option 5 N

In your opinion what is the clinical need for: Circulating biomarkers as surrogate endpoints for clinical trials Very high (high clinical need, development urgently needed) High (relevant clinical need) Low (not key priority for this purpose) Abstain/Unqualified to answer Detailed voting results Option 1 13 Option 2 1 Option 3 4 Option 4 N 18

For which clinical situation is the development of circulating biomarkers as surrogate endpoints for clinical trials most relevant? Population-based screening for prostate cancer Localised/locally-advanced prostate cancer Recurrence after radical treatment Metastatic prostate cancer Abstain/Unqualified to answer Detailed voting results Option 1 Option 2 1 Option 3 Option 4 16 Option 5 N 18

Which assay is most important as a biomarker of progression for clinical management in men with mCRPC? CTC enumeration AR-V7 detection PSA rise Radiographic progression Clinical progression All of the above Abstain/unqualified to answer Detailed voting results Option 1 2 Option 2 Option 3 1 Option 4 Option 5 4 Option 6 9 Option 7 N 18

If all tests were available, which one would you recommend in the following clinical situations (best performing assay): 31.Men with high-risk localised/locally-advanced prostate cancer Cell-free DNA quantification Cell-free DNA quantification and sequencing CTC enumeration AR-V7 None Abstain/Unqualified to answer Detailed voting results Option 1 Option 2 5 Option 3 2 Option 4 Option 5 8 Option 6 N 17

If all tests were available, which one would you recommend in the following clinical situations (best performing assay): 32.Man with rising PSA after radical local treatment (biochemical recurrence) Cell-free DNA quantification Cell-free DNA quantification and sequencing CTC enumeration AR-V7 None Abstain/Unqualified to answer Detailed voting results Option 1 Option 2 2 Option 3 1 Option 4 Option 5 14 Option 6 N 18

If all tests were available, which one would you recommend in the following clinical situations (best performing assay): 33.Man with newly diagnosed metastatic prostate cancer Cell-free DNA quantification Cell-free DNA quantification and sequencing CTC enumeration AR-V7 None Abstain/Unqualified to answer Detailed voting results Option 1 Option 2 11 Option 3 2 Option 4 Option 5 4 Option 6 N 17

If all tests were available, which one would you recommend in the following clinical situations (best performing assay): 34.Man with metastatic CRPC Cell-free DNA quantification Cell-free DNA quantification and sequencing CTC enumeration AR-V7 None Abstain/Unqualified to answer Detailed voting results Option 1 Option 2 12 Option 3 4 Option 4 1 Option 5 Option 6 N 18

CTC phenotyping and genotyping Very high (high clinical need, development urgently needed) High (relevant clinical need) Low (not key priority for this purpose) Abstain/Unqualified to answer Detailed voting results Option 1 11 Option 2 5 Option 3 2 Option 4 N 18

AR-variant assays Very high (high clinical need, development urgently needed) High (relevant clinical need) Low (not key priority for this purpose) Abstain/Unqualified to answer Detailed voting results Option 1 6 Option 2 10 Option 3 2 Option 4 N 18

Neuroendocrine biomarker analyses Very high (high clinical need, development urgently needed) High (relevant clinical need) Low (not key priority for this purpose) Abstain/Unqualified to answer Detailed voting results Option 1 4 Option 2 7 Option 3 6 Option 4 1 N 18

PTEN loss analyses Very high (high clinical need, development urgently needed) High (relevant clinical need) Low (not key priority for this purpose) Abstain/Unqualified to answer Detailed voting results Option 1 3 Option 2 4 Option 3 9 Option 4 1 N 17

DNA repair defect analyses Very high (high clinical need, development urgently needed) High (relevant clinical need) Low (not key priority for this purpose) Abstain/Unqualified to answer Detailed voting results Option 1 16 Option 2 1 Option 3 Option 4 N 17

RB1 loss Very high (high clinical need, development urgently needed) High (relevant clinical need) Low (not key priority for this purpose) Abstain/Unqualified to answer Detailed voting results Option 1 2 Option 2 8 Option 3 6 Option 4 1 N 17

MMR/MSI signatures Very high (high clinical need, development urgently needed) High (relevant clinical need) Low (not key priority for this purpose) Abstain/Unqualified to answer Detailed voting results Option 1 12 Option 2 4 Option 3 1 Option 4 N 18

Immunological biomarker studies (eg PD-L1, PD-L2) Very high (high clinical need, development urgently needed) High (relevant clinical need) Low (not key priority for this purpose) Abstain/Unqualified to answer Detailed voting results Option 1 7 Option 2 6 Option 3 5 Option 4 N 18

Prostate cancer focused, targeted next generation sequencing gene panel Very high (high clinical need, development urgently needed) High (relevant clinical need) Low (not key priority for this purpose) Abstain/Unqualified to answer Detailed voting results Option 1 12 Option 2 6 Option 3 Option 4 N 18

Prostate cancer focused, targeted MiR profiling Very high (high clinical need, development urgently needed) High (relevant clinical need) Low (not key priority for this purpose) Abstain/Unqualified to answer Detailed voting results Option 1 Option 2 3 Option 3 13 Option 4 1 N 17

HEALTHY VOLUNTEER DATA Very high importance High importance Low importance Not important Abstain/Unqualified to answer Detailed voting results Option 1 11 Option 2 5 Option 3 1 Option 4 Option 5 N 17

REPRODUCIBILITY STUDIES Very high importance High importance Low importance Not important Abstain/Unqualified to answer Detailed voting results Option 1 17 Option 2 Option 3 Option 4 Option 5 N

VARIABILITY STUDIES Very high importance High importance Low importance Not important Abstain/Unqualified to answer Detailed voting results Option 1 15 Option 2 1 Option 3 Option 4 Option 5 N 16

COMPARISON OF DIFFERENT PLATFORMS Very high importance High importance Low importance Not important Abstain/Unqualified to answer Detailed voting results Option 1 7 Option 2 5 Option 3 3 Option 4 1 Option 5 N 16

QUALIFICATION INVOLVING PROSPECTIVE CLINICAL TRIALS Very high importance High importance Low importance Not important Abstain/Unqualified to answer Detailed voting results Option 1 14 Option 2 3 Option 3 Option 4 Option 5 N 17

HEALTH ECONOMIC ANALYSES Very high importance High importance Low importance Not important Abstain/Unqualified to answer Detailed voting results Option 1 11 Option 2 5 Option 3 1 Option 4 Option 5 N 17