ESMO ADVANCED COURSEClinical Questions in Prostate Cancer

Name Dr. Darren MC Poon

Date 6 Sep 2019

Rising PSA, what to do?

Dr. Darren MC Poon

ConsultantDepartment of Clinical Oncology

Prince of Wales HospitalThe Chinese University of Hong Kong

Vice-president of Hong Kong Society of Uro-Oncology

Disclosure Advisory board: Janssen, Ipsen, Astellas Speaker honorarium: Roche, BMS, Merck, Pfizer, MSD

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SCOPE

1. Defining biochemical progression1. After local treatment – RT/Surgery2. After systemic treatment

2. Natural history of biochemical progression1. Specific prognostic +/- predictive factors

3. Diagnostic evaluation after biochemical progression1. Conventional vs novel imaging

Different states of prostate cancer

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ClinicallyLocalized

disease

Rising PSA

Non-metastaicHormonal-sensitive disease

Metastatic Hormonal-sensitive Disease (mHSPC)

Non-metastaic Castration-resistant disease (M0 CRPC)

Metastatic Castration-resistant disease (mCRPC)

ADT (IAD vs CAD)

De Novo mHSPC

Definition of detectable post-RP PSA & ART vs SRT(ASTRO/AUA guidelines)

Biochemical (PSA) recurrence (i.e. detectable PSA level) Detection of PSA ≥ 0.2ng/ml

Post-RP (6-13 weeks) should have undetectable PSA level (i.e. <0.2) With a second confirmatory level detected at ≥ 0.2mg/ml

Adjuvant RT (ART) Post-RP RT for patients with higher risk of recurrence (adverse pathological factors) With undetectable PSA (i.e. absence of detectable residual)

Salvage RT (SRT) RT to prostate bed +/- LNs in patients with PSA recurrence (detectable PSA) after surgery but no evidence of DM

Adjuvant and salvage radiation therapy after prostatectomy: ASTRO/AUA guidelines IJROBP May 2013

566 men who had undergone radical prostatectomy3 groups:1) Undetectable (74%)

1) (PSA ≤0.03 ng/mL)2) Low detectable – Stable (16%)

1) (PSA >0.03 but <0.2 ng/mL)3) Low detectable – Unstable (10%)

1) (PSA >0.03 but <0.2 ng/mL & two subsequent increases in serum PSA and/or a PSA velocity of ≥0.05 ng/year)

4) Primary end point: Biochemical recurrence (PSA≥0.2ng/ml) beyond 3 yrs of FU

WHAT ABOUT POST-RP RISING PSA BUT <0.2?

J Urol. 2014 Nov

p <0.0001

Importance of pre-SRT PSA in patients with adverse pathological features

716 node-negative post-RP patients with early SRT (Pre-SRT PSA ≤ 0.5)

Adverse pathological factors:

pT3 disease GS ≥8, +ve surgical margin

Increased risk of BCR for every 0.1 ng/ml PSA

0 – 1 risk factor: 1.5% ≥2:risk factor: 10%

0-1 risk factors

≥2 risk factors

Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy. Eur Urol Oct 2015

CHALLENGES IN INTERPRETING POST-RT PSA

1) Normal prostatic glandular tissue remains1) Post-RT PSA usually ‘detectable’2) Affected by the benign prostatic disease/conditions

2) Interplay between RT and ADT1) ADT suppress PSA level may create post-RT ‘false-negative’ PSA response

3) Takes time to reach post-RT PSA nadir1) Usually at 1-2 yrs after RT2) No absolute PSA nadir to define ‘success’ of RT

4) ‘False-positive’ PSA rising1) PSA bounce effect

4839 patients with T1-2 Pca with EBRT alone at 9 institutions between 1986 and 1995

Post-RT PSA bounce:- Minimal rise of 0.4 ng/mL followed by a drop in PSA level of any magnitude

POST-RT PSA BOUNCE EFFECT

ASTRO BP definition:3 consecutive PSA rises after nadir

Cancer. 2006 Oct

- Post-RT biochemical failure: PSA rise of 2 ng/mL or more above the nadir (regardless of ADT or not)- Date of failure: Time the rise in PSA is noted

POST-RT BIOCHEMICAL PROGRESSIONPhoenix criteria: post-RT nadir + 2ng/ml

Int J Radiat Oncol Biol Phys. 2006 Jul

PRE-/POST-TREATMENT PROGNOSTIC FACTORS IN BCR PCA

Urol Int. 2018

PSA doubling time (PSADT) and the risk of metastasis

13 Smith JCO 2013

BIOCHEMICAL RECURRENCE AFTER CURATIVE TREATMENT: EAU LOW- VS HIGH-RISK EAU Low risk EAU high risk

ProstatectomyPSA-DT > 1yr AND <1yr OR

Pathological ISUP grade <4 4-5

RadiotherapyInterval to biochemical failure >18 months AND <18 months OR

Biopsy ISUP grade <4 4-5

Low riskLow risk

High riskHigh risk

metastatic progression (MP)-free survival Prostate-cancer specific survivalVan den Broeck et al. Eur Urol 2019 Jun; Tilki D et al. Eur Urol 2019 Jun

Genomic classifier- RNA extraction and microarray hybridization- Focus on 22 specific markers- GC score will be calculated- Higher the score, higher the risk of recurrence

Post-RP detectable PSA

PLoS One, 2013; Eur Urol. 2018 Jul

GENOMIC CLASSIFIER : ART VS SRT

GC <0.4 GC >0.4

Cumulative incidence of distant metastasisART 6% vs SRT 23%

R Dan et al. JCO Mar 2015 Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy

Treatment landscape for prostate cancer 2019

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ClinicallyLocalized

disease

Rising PSA

Non-metastaicHormonal-sensitive disease

Metastatic Hormonal-sensitive Disease (mHSPC)

Non-metastaic Castration-resistant disease (M0 CRPC)

Metastatic Castration-resistant disease (mCRPC)

DocetaxelAbirateroneEnzalutamideApalutamide

ApalutamideEnzalutamideDarolutamide

Docetaxel / Radium-223Chemo-naïve: Abi/Enza/Spileucel-TPost-chemo: Abi/Enza/Cabazitaxel

Olaparib / Rucaparib (BRCA/HRD)Pembrolizumab (MSI +ve)Lu-177 PSMA ?

ADT (IAD vs CAD)

Prostate RT

Metastasis-directedTherapy?

Metastasis-directedTherapy?

De Novo mHSPC

APCCC consensus Stop treatment when at

least two of three criteria to be fulfilled 1. PSA progression 2. Radiographic

progression 3. Clinical deterioration

Prostate Int 2017; JCO 2016; Ann Oncol 2015

PCWG3

PSA FLARE: LOCAL EXPERIENCE ON ABIRATERONE

PSA flare can be defined as an initial rise in serum PSA under therapy, followed by a drop to values belowbaseline.1

But PSA flare does not necessarily cause clinically relevant issues.1,2

Local study:3 >50% of mCRPC patients on abiraterone with initial PSA flare had ultimate PSA response toabiraterone. No substantial difference in clinical outcomes in patients with or without PSA flare.

Temporary PSA increase during initial systemic treatment should be monitored for a sufficient period (i.e. threemonths) to avoid early withdrawal from treatment.

1. Olbert PJ et al. Anticancer Drugs 2006; 17: 993-6. 2. Burgio SL et al. Clin Genitourin Cancer 2015; 13: 39-43. 3. Poon DM et al. BMC Urol 2016; 16: 12.

DIAGNOSTIC EVALUATION FOR biochemical progression

PSMA-PET VS BONE SCAN

A 67-year-old patient with mCRPC: PSA level 500 ng/ml.

Bone scan PSMA-PET scan

PSMA-PET scan: Higher sensitivity and specificity to Bone scan

Eur J Nucl Med Mol Imaging (2016) 43:2114–2121

PSMA-PET VS BONE SCAN + CT

238 pts with BCR after RP/RT- BS/CT: -ve or oligometastatic disease- Re-staging with PSMA-PET- Median PSA: 2.55 ng/ml

NOVEL IMAGING FOR PROSTATE CANCER

DETECTION RATE OF PET/CT WITH VARIOUS TRACERS

7-44% 25-67% 63-89%

29-67% 46-93% 71-93%

21-41% 46-78% 55-86%

Meta-analysis with 4790 PCa pts for primary and secondary staging with PMSA-PET scan

+ve scans with various PSA levels:- <0.2: 33%- <0.5: 45%- <1: 59%- <2: 75%- ≥2: 95%

J Urol. 2019 Apr; Eur Urol. 2019 Feb 14

68GA-PSMA VS 18F-FLUCICOLVINE PET

- 50 patients with post-RP biochemical recurrence with PSA : 0·2 to 2·0 ng/mL

- 3 independent masked readers for interpretation of 68Ga-PSMA vs 18F-flucicolvine PET

+ve scan/findings: Consensus majority

interpretation was generated (two vs one)

Lancet oncology 2019

M0 CRPC - Endangered ‘species’ from extinction

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M0 CRPC

M0 CRPC ? With PSMA-PET scan

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- 8825 records from 6 high-volume PET centres were screened (Australia, Germany, USA)

- 200 patients were identified meeting the following inclusion criteria:- CRPC during ADT and PSA > 2ng/mL- PSADT ≤ 10 months or Gleason score ≥ 8- No known metastases on prior assessment (including CT/MRI and bone scans)

- Primary end point was detection rate by PSMA-PET for local/pelvic disease and distant metastases disease

Courtesy: Prof. Michael Hofman

Lesion Detection by PSMA PET

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• 196/200 (98%) patients positive on PSMA-PET:

– 54% had N1 disease– 55% had M1 disease

a) Lung (n = 4), liver (n = 5), peritoneum (n = 4), connective tissue (n = 1)The size of the red circles is proportional to lesion prevalence.

Local Tx ? Systemic Tx

Case example in mCRPC 64/M 2011: Metastatic CA prostate with bone mets. GS

3+4. Started ADT Apr 2015: developed mCRPC: Started abiraterone

PSA Apr 29 2015 5.7 * <Abiraterone started since 29/4/2015> May 21 2015 3.13 Jul 02 2015 2.77 Sep 10 2015 <0.03 Dec 02 2015 <0.03 Feb 25 2016 <0.03 May 27 2016 <0.03 Sep 01 2016 <0.03 Nov 25 2016 <0.03 Mar 02 2017 <0.03 Jun 08 2017 <0.03 Aug 31 2017 <0.03 Nov 23 2017 <0.03 Mar 01 2018 <0.03 Jun 20 2018 0.32 Aug 14 2018 1.10 Sep 15 2018 4.8

• PSMA-PET scan (Sep 2018):– PSMA avid bony lesions are found at T1 vertebral body and

proximal right femur.

SBRT in oligo-progression of mCRPC SBRT to T1 & R femur : 16Gy x 1 fraction

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PSA: Sep 15 2018 4.8 <SBRT in T1 & R femur completed in Sep 2018> Oct 11 2018 0.37 Dec 04 2018 <0.03

PSMA-PET scan (3/12/2018): T1 and proximal right femur: No residual uptake No other new lesion

Still continue abiraterone (latest follow-up: May 2019)

EAU GUIDELINE 2019

Post-RP

Post-RT

APCCC 2019

CONCLUSION- Definition of biochemical progression varies in different scenarios

- Post-RP: PSA ≥0.2- Post-RT: PSA nadir + 2- Post-systemic treatment: PCWG3 definition

- Biochemical progression ≠ Treatment- Identify high risk group and consider for further systemic treatment- APCCC: 2 out of 3 (biochemical/clinical/radiological) progression > stop treatment in advanced PCa

- Role of conventional imaging (e.g. CT, bone scan) is being challenged by novel imaging- Need more data to validate while the treatment paradigm is evolving with novel imaging - Novel imaging may be reserved in situations with equivocal findings by conventional imaging

Thank you for your attention

Email: mc_poon@clo.cuhk.edu.hkTwitter: @DrDarrenPoon