ESMO VIRTUAL ADVANCED COURSE

ON CLINICAL QUESTIONS IN
PROSTATE CANCER
Clinical Case: metastatic CRPC

Dr Pernelle LAVAUD, MD
30-31 March 2022
DECLARATION OF INTERESTS

Travel accommodation: Ipsen, Mundi Pharma, Janssen, Astellas, Pfizer

Consulting/Advisory : Astellas, AstraZeneca, Sanofi, Janssen

Dr Pernelle LAVAUD Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
MR DEF. , 63 YEARS OLD

2001:
Rhumatologist
No smoking history

Hypertension (Amlodipine, Atenolol)

Hepatitis B 30 years ago

Family history:
- maternal grand-uncle: Prostate cancer
- father: Glioblastoma

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PROSTATE CANCER HISTORY

From 2001: PSA around 6.2ng/ml with negative biopsies

April 2009:
- OMS 0, no pain, pollakiuria
- PSA 8.76,
- Biopsy: prostatic adenocarcinoma, Gleason 8 (4+4)

Staging:
- 1 bone metastatis
- T2cN0M1b

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WHAT IS YOUR TREATMENT ?

Hormone-naive prostate cancer, low volume / low risk

1) Castration alone

2) Castration + 1st generation AR antagonist

3) Castration + radiotherapy (prostate + bone metastasis)

4) Castration + AR-axis inhibitor

5) Castration + AR-axis inhibitor + chemotherapy

6) Other ?

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 NO MEANINGFUL BENEFIT FROM « COMPLETE ANDROGEN BLOCKADE » OR
ZOLEDRONIC ACID IN M1 CSPC

US trial, n=645
STAMPEDE, n=1777

Prostate Cancer Trialists' Collaborative Group. Lancet. 2000; 355: 1474-5.

James N, Lancet 2016; 387: 1163-77

Smith MR, J Clin Oncol 2014; 32: 1143-50

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 CHAARTED: OS BY DISEASE EXTENT (VOLUME)

Sweeney C, et al. N Engl J Med. 2015;373:737-746. Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
 NEXT GENERATION AR TARGETING IMPROVES OS
REGARDLESS OF LOW/HIGH BURDEN

STAMPEDE (Abi)

TITAN (Apa)

ENZAMET (Enza)

Hoyle A, ESMO 2018; Chi K, NEJM 2019, Davis I, NEJM 2019 Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
 PEACE 1 TRIAL
ADT+DOC +/- ABI (+/- RXT) POPULATION: RPFS

SOC+Abi SOC SOC+Abi SOC

« High Volume » « Low Volume » (n = 129) (n = 122)
(n = 225) (n = 231)
Median, y (95% CI) 4.1 (2.7-NE) 1.6 (1.4-2.0) Median, y (95% CI) NE (3.1-NE) 2.7 (2.5-NE)
Events 97 156 Events 41 55
HR (95% CI)* 0.47 (0.36-0.60) HR (95% CI)* 0.58 (0.39-0.87)
100% P value < 0.0001 100% P value 0.006
Radiographic progression-free survival

Radiographic progression-free survival

80% 80%

60% 60%

40% 40%

20% 20%

0% 0%
0 1 2 3 4 0 1 2 3 4
Time from randomization (in years) Time from randomization (in years)
No Yes No Yes
No 231 162 71 35 8 No 122 110 65 25 8

Yes 225 182 107 66 24 Yes 129 120 93 39 11

*Adjusted on stratification parameters (RXT, PS, type of castration, metastatic burden)

◆ Karim Fizazi, ESMO 2021 Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
 OVERALL SURVIVAL: PROSTATE RADIOTHERAPY IN M1 (STAMPEDE)

Low burden High burden

1.0

1.0

0.8
SOC+RT
0.8

SOC SOC
0.6
Overall survival

0.6

Overall survival
0.4
SOC+RT
0.4

trt = SOC by Kaplan Meier

0.2 trt = SOC by Kaplan Meier
trt = SOC+RT by Kaplan Meier 0.2
trt = SOC+RT by Kaplan Meier
SOC by flexible parametric model
SOC by flexible parametric model
SOC+RT by flexible parametric model
0.0 SOC+RT by flexible parametric model
0.0
0 6 12 18 24 30 36 42 48 54
Time from randomisation (Months) 0 6 12 18 24 30 36 42 48 54
Time from randomisation (Months)
Number of
patients (events) Number of
patients (events)

SOC 409 (5) 400 (9) 387 (17) 361 (17) 265 (12) 217 (22) 155 (16) 110 (8) 67 (5) 25 SOC 567 (11) 547 (42) 500 (58) 428 (41) 312 (27) 245 (43) 161 (20) 100 (7) 48 (3) 13
SOC+RT 410 (1) 405 (4) 399 (12) 366 (12) 301 (19) 242 (10) 200 (15) 137 (11) 77 (5) 24 SOC+RT 553 (10) 537 (38) 487 (48) 424 (59) 282 (30) 216 (31) 146 (19) 90 (14) 44 (5) 20

HR: 0.68 (95% CI 0.52-0.90); p=0.007 HR: 1.07 (95% CI 0.90-1.28); p=0.420
3 year OS (%): 3 year OS (%):
SOC = 73% SOC = 54%
SOC+RT = 81% SOC+RT = 53%
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Parker C, ESMO 2018 and Lancet 2018
TREATMENT OF OLIGOMETS SHOWED BENEFIT
COMPARED TO OBSERVATION

ORIOLE trial (SABR vs observation): PFS STOMP trial (local treatment vs observation):
ADT-free survival

P. Ost et al. ; JCO 2018

R. Philips et al. ; JAMA Oncol 2020 Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
TREATMENT

- May 2009: Hormonotherapy by LH-RH analogue + antiandrogen (3 weeks)

- June 2009: Bone met radiotherapy

-> Good PSA response: 13 -> 0.5 (Aug 2009)

March 2010: Elevation of PSA: 0,781 ng/ml confirmed on the next blood tests. Normal scan

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WHAT WILL YOU DO ?

1) Wait for a more « meaningfull » progression

2) Add an AR-axis targeted inhibitor

3) Local treatment of the prostate

4) Zoledronic acid

5) Other ?

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TREATMENT

- May 2009: Hormonotherapy by LH-RH analogue + antiandrogen (3 weeks)

- June 2009: Bone met radiotherapy

-> Good PSA response: 13 -> 0.5 (Aug 2009)

March 2010: Elevation of PSA: 0,781 ng/ml – Body /bone scan negatives

April 2010: radiotherapy of the prostate

-> PSA response: 0.5 (Nov) > 0.21 (Jun 2011) > 0.101 (Apr 2011)

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TREATMENT
Sept 2012: New elevation of PSA
Prostatic MRI + Body scan and bone scan: intraprostatic relapse: addition of bicalutamide

Jun 2013: PSA 6.8 (biological progression only)

Enzalutamide
Mar 2014: Phase II trial with Sipuleucel T : Sipuleucel T
C1 28/03/2014; C3 25/04/2014

Sep 2014: PSA increase, body scan: no met

Nov 2014: Enzalutamide

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MOLECULAR PROFILING

Nov 2015: new PSA increase (from 2 to 4 ng/ml in 3 months) – negative scan

Prostate biopsy with sequencing:

CDK12 R329* (12,6 %), L781* (9,2 %)

BRAF JHDM1D-BRAF fusion (3,6 %)
CCND1 amplification - equivocal
AR amplification - equivocal
ASXL1 Q546* (0,71 %)
FGF19 amplification - equivocal
FGF3 amplification - equivocal
FGF4 amplification - equivocal
FLCN W306* (48 %)

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WHAT IS YOUR RECOMMANDATIONS ?

1) Continuation of Enzalutamide

2) New local treatment of the prostate

3) Abiraterone

3) Docetaxel

4) Other

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 CROSS-RESISTANCE BETWEEN ABIRATERONE AND
ENZALUTAMIDE

nd
Author Year N pts Duration of 2  PSA Median PFS
published treatment ≥ 50%
ENZ →ABI
Loriot et al. 2013 38 3 mo 8% 2.7 mo
Noonan et al. 2013 30 13 wks 3% 3.6 mo
ABI → ENZ
Schrader et al. 2013 35 4.9 mo 29% 4.0 mo
Badrising et al. 2014 61 3 mo 21% 2.8 mo
Bianchini et al. 2014 39 2.9 mo 23% 2.8 mo
Schmid et al. 2014 35 2.8 mo 10% 3.1 mo
Brasso et al. 2014 137 3.2 mo 18% -

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Zhang T et al. Expert Opin Pharmacotherap 2014;16:1-9
IF THE TWO AR AXIS TARGETED AGENTS ARE TO BE USED
SEQUENTIALLY, THE ABI-ENZA SEQUENCE IS LIKELY TO BE PREFERRED

2-PSA-PFS OS

Abi then Enza

Enza then Abi

Khalaf D, Lancet Oncol 2019; 20: 1730-39

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 TREATMENT

Apr 2016: Abiraterone

Aug 2016: PSA progression, Body scan + MRI: prostatic signal only
Corticosteroid-induced diabatesis
CDK12 R329* (12,6 %), L781* (9,2 %)
BRAF JHDM1D-BRAF fusion (3,6 %)
Sept 2016: Dabrafenib 150mg x 2 (compassional access)
CCND1 amplification - equivocal
PSA baseline 14ng/ml -> 4 ng/ml
AR amplification - equivocal
ASXL1 Q546* (0,71 %)
PSA progression after 6 mo
FGF19 amplification - equivocal
Mar 2017: 6.4 Apr2017: 10,7 ng/ml
FGF3 amplification - equivocal
Aug 2017: Addition of Trametinib 2mg (PSA baseline 15.5ng/ml)
FGF4 amplification - equivocal
Continuation of PSA progression (Dec 2017: 80 ng/ml)
FLCN W306* (48 %)

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TREATMENT

Feb 2018: stop dabrafenib + trametinib

-> Withdrawal syndrome with decrease of PSA (98 -> 62ng/ml)

Aug 2018: PSA progression

Sep 2018: rechallenge with enzalutamide
-> PSA baseline 90 -> 50 (Oct) -> 60 (Dec)

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WHAT IS YOUR TREATMENT

1) Docetaxel CDK12 R329* (12,6 %), L781* (9,2 %)

BRAF JHDM1D-BRAF fusion (3,6 %)
2) PSMA lutetium CCND1 amplification - equivocal
AR amplification - equivocal
3) PARP inhibitors ASXL1 Q546* (0,71 %)
FGF19 amplification - equivocal
4) Clinical trial with immunotherapy FGF3 amplification - equivocal
FGF4 amplification - equivocal
FLCN W306* (48 %)

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RUCAPARIB IN HRD+ MCRPC

ESMO 2018
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Exploratory analysis gene-by-gene rPFS
PROfound TRITON 2
n=
81 10.84 (9.17, 13.08)
BRCA2
47 3.48 (1.74, 3.65)

61 5.09 (3.61, 5.52)

CDK12
28 2.20 (1.71, 4.83)

62 5.36 (3.61, 6.21)

ATM
24 4.70 (1.84, 7.26)

8 2.07 (1.38, 5.52)

BRCA1
5 1.84 (1.71, 3.71)
ATM
7 5.59 (1.64, 11.99)
CHEK2
5 3.35 (1.38, NR)

6 2.69 (1.77, 3.91)

PPP2R2A
4 NR

4 10.89 (1.61, 14.75)

RAD51B
1 1.77
Frequency

3 7.20 (3.71, 7.39)

RAD54L
2 2.41 (1.81, 3.02)

0 2 4 6 8 10
Olaparib Physician's choice
CDK12 CHEK2 Others
Median rPFS (95% CI)
Olaparib Physician’s choice Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
Hussain M, ESMO 2019 Abida W, Clin Cancer Res 2020
TREATMENT

May 2019: basket trial with Atezolizumab

Atezolizumab

TURP

Fev 2020: PSA progression

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TREATMENT

Sept 2020: Taxotere

PSA baseline 144 -> Feb 2021 78 -> Apr 2021 171

Apr 2021 : Cabazitaxel (C9 07/10/2021)

PSA response
Pain relief

4/01/2022: hepatic progression, PSA 247

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WHAT IS YOUR NEXT TREATMENT ?

Patient OMS 1
Symptoms: pollakiuria, hematuria, pelvic pain
Chronic kidney failure (cl 30 ml/mi)

1) Rechallenge with AR-axis inhibitors ?

2) Rechallenge with taxanes?

3) PARP inhibitors

4) Carboplatin

5) PSMA lutetium

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PLATINUM-BASED THERAPY IN MEN WITH METASTATIC CASTRATION
RESISTANT PROSTATE (MCRPC) WITH OR WITHOUT DNA REPAIR DEFECTS –
A MULTICENTRE RETROSPECTIVE ANALYSIS

abstract #2903 ESMO 2018, S. Gillessen

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 TREATMENT Cabazitaxel rechallenge

Feb 2022: rechallenge of CABAZITAXEL

Treatment still ongoing …

Docetaxel rechallenge

Oudard S. BJU Int. 2015 May;115(5):744-52 C. Thibault et al; EJC 2018

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Thank you for your attention

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