m0 crpc: where are we in 2018? · (3a) no recommenda tion maintain castrate serum levels of...

M0 CRPC: Where are we in 2018?

Ravindran KANESVARAN, MD

Disclosures

• Speaker Bureau: Pfizer, J&J, Sanofi, Novartis, MSD, Eisai, Astellas

• Advisory Board/ Consultant: GSK, Novartis, Bayer, J&J, Mundipharma, Astellas, MSD, BMS, Eisai, Amgen

• Research support: Sanofi, J&J, Astellas

Case Study

• Mr PKL is a 68 year old gentleman who presented to urology after a raised screening PSA of 11.2

• He was found to have an enlarged prostate on DRE and TRUS biopsy revelaed a G 4+3 acinar adenocarcinoma

• MRI prostate : localised prostate cancer

• Proceeded to have a RT+ADT in July 2014 ( PSA nadir 0.1)

• He had ADT continued post RT

• PSA started to rise while on ADT and in Jan 2015 reached 4.0

• CT TAP and bone scan : No evidence of disease (NED)

What is nmCRPC?

Localized or locally

advanced prostate

cancer

Biochemical

recurrence

nmCRPC

Primary

progressive

mHSPC

Newly diagnosed

mHSPC

mCRPCTerminal disease

(death)

First prostate cancer diagnosis

Adapted from: Scher HI et al. J Clin Oncol. 2016;34(12):1402-1418; Mottet, N, et al. (2017). EAU - ESTRO - ESUR - SIOG Guidelines on Prostate Cancer. Available from: http://uroweb.org/guideline/prostate-cancer/ (Access Date: August 2017); Hong JH, Kim IY. Korean J Urol. 2014 Mar;55(3):153-60

Non-metastatic

Metastatic

Biochemical progression

while on ADT+

Serum testosteronelevels below 50

ng/dL+

No evidence of metastasis

Who are the patients with high risk nmCRPC?

• One of the strongest predictors of metastasis and death is the PSA doubling time (PSADT), a mathematical determination of the length of time (in months) needed for the PSA level to double in a given patient1

• Short PSADT has been consistently associated with higher risk to first (bone) metastasis or death3,4 � HIGH RISK population

• Patients with high-risk nmCRPC have a shorter PSADT and a higher risk of metastasis4,5

1. Paller CJ et al. Clin Adv Hematol Oncol. 2013;11(1):14-23; 2. Arlen PM, et al. J Urol. 2008 Jun;179(6):2181-5; 3. Smith MR, et al. J Clin Oncol. 2013 Oct 20;31(30):3800-6; 4. Freedland SJ, et al. J Clin Oncol. 2007 May 1;25(13):1765-71; 5. Howard LE et al. BJU Int. 2017 Nov;120(5B):E80-E86.

PSA doubling time is calculated by log(2) divided by the slope of the linear regression of log(PSA) over time in months2

PSA doubling time as predictor of outcomes� Data on 441 men with nmCRPC in 2000–2015 at five Veterans Affairs hospitals

� Cox models used to test the association between log-transformed PSADT and the development of metastasis, all-cause mortality and PC-specific mortality

Conclusions• PSADT was a strong predictor of metastases, all-cause mortality and PC-specific mortality in patients with nmCRPC

• These thresholds can be used for selecting high-risk men for clinical trials.

Howard LE, et al. BJU Int 2017; 120: E80–E86

Compared with PSADT ≥15 months

Predictor of metastases Predictor of PCSM Predictor of ACM

HR 95% CI HR 95% CI HR 95% CI

PSADT 9–14.9 mo. 1.33 0.87–2.02 1.59 1.03–2.47 1.42 1.02–1.96

PSADT 3–8.9 mo. 3.30 2.41–4.51 2.90 2.04–4.13 1.98 1.51–2.61

PSADT <3 mo. 10.0 5.93–16.9 12.4 7.25–21.2 5.83 3.72–9.12

Predictor of metastases Predictor of PC-specific mortality Predictor of all-cause mortality

What would you do at this point in time? (2018)

a) Start secondary hormonal therapy ( apalutamide or enza)

b) Watch and wait

c) Clinical Trial

d) Chemotherapy

Summary of PC Guidelines prior to 2018

1. Mottet, N, et al. (2017). EAU - ESTRO - ESUR - SIOG Guidelines on Prostate Cancer. Available from: http://uroweb.org/guideline/prostate-cancer/ (Access Date: August 2017); 2. Parker C, et al. Ann Oncol. 2015;26(suppl 5):v69-v77; 3. NCCN Clinical Practice Guidelines in Oncology – Prostate Cancer. Version 2-2017 – Feb 11,

2017; 4. Lowrance WT, et al. J Urol. 2016;195:1444-1452.

EAU 20171 ESMO 20152 NCCN V2.20173 AUA 20154

Do not treat patients for nmCRPC outside of a clinical trial (3A)

No recommendation

Maintain castrate serum levels of testosterone plus one of the following- Clinical trial (preferred)- Observation especially

if PSADT ≥10 mo- Secondary hormone

therapy especially if PSADT < 10 mo

- Antiandrogen- Antiandrogen withdrawl- Ketokonazole

±hydrocortisone- Corticosteroid- DES or other estrogen

1. Clinicians should recommend observation with continued ADT to patients with nmCRPC. (Recommendation; Evidence Level Grade C) 2. Clinicians may offer treatment with first- generation anti-androgens (flutamide, bicalutamide and nilutamide) or first generation androgen synthesis inhibitors (ketoconazole+steroid) to select patients with nmCRPC who are unwilling to accept observation. (Option; Evidence Level Grade C) 3. Clinicians should not offer systemic chemotherapy or immunotherapy to patients with nmCRPC outside the context of a clinical trial. (Recommendation; Evidence Level Grade C)

APCCC 2015Treatment of nmCRPC

Gillessen S, et al. Ann Oncol. 2015 Aug;26(8):1589-604.

When do you recommend initiating additional treatment for M0 CRPC patients (negative imaging, rising PSA, outside of clinical trials) apart from maintaining ADT?

1. Not for M0

2. Based on PSA doubling time

3. Based on absolute PSA value

4. Based on combination of PSA doubling time and absolute PSA

5. Abstain

6. Unqualified to answer

• Most panelists acknowledged that withholding additional treatment in a patient who knows that his PSA is rising on ADT can be challenging even without supporting data that any therapy in this stage impacts OS.

NCCN Clinical Practice Guidelines in Oncology – Prostate Cancer. Version 4.2018

For unsolicited request from HCPs only. MA-ATH_XTD_02/2018-001

MFS as an endpoint in nmCRPC

1. Schweizer MT et al. Ann Oncol. 2013;24(11):2881-2886; 2. Xie W, et al. J Clin Oncol. 2017:JCO2017739987.

• There are challenges in conducting trials in earlier patient populations due to the long natural history of prostate cancer1

• MFS might be a more attractive proximal end point to use when designing trials in patients in earlier disease stages1

• Compared with OS, MFS occurs earlier and is not influenced by therapies given after the development of metastases1

• MFS is an important new end point that can be robustly and reliably assessed, has internal consistency, and relates to clinically relevant end points (eg, time to distant metastasis, time to death)2

• MFS has been shown to be a strong surrogate of OS in prostate cancer patients at significant risk of death from prostate cancer, regardless of the primary localized therapy2

Time interval from PSA recurrence (or start of trial/randomization) to first radiographic metastasis or death

Metastasis-free survival1,2=

MFS is associated with OS in men with PSA-recurrent PC treated with deferred ADT

Schweizer MT et al. Ann Oncol. 2013;24(11):2881-2886

• Retrospective analysis of 450 men with BRPC following prostatectomy of which 140 developed subsequent metastases.

• ADT was deferred until after the development of metastases.

• Cox regression models were developed to investigate factors influencing OS.

Conclusions:• MFS emerged as an independent predictor of OS• MFS may be a reasonable intermediate end point in future clinical trials

Multivariable Cox proportional hazards model for OS from the time of first metastasis

MFS is a strong surrogate of OS in localized PC

� The advantage of using a surrogate, such as MFS, rather than OS is the ability to observe the number of required events earlier

� Use of MFS can allow an expeditious evaluation of a new therapy if it has a meaningful treatment effect on MFS

Xie W, et al. J Clin Oncol. 2017;35:3097-3104.

OS rate at 8-year vs MFS rate at 5 years

Treatment effects (HR) on OS vs treatment effects on MFS (HR)

Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

70%

60%

SPARTAN

Primary Endpoint: MFS

Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

70%

50%

PROSPER


60%

Time to PSA Progression


70%

Time to First Use of New Antineoplastic Therapy


SurgerySpartan vs Prosper

Mateo et al., Eur Urol, 2018

Adverse Events of Special Interest*

Differential side effects

What we did in 2016?

• Upon discussion with patient – agreed to enrol into PROSPER

• Screened and randomised into study

• Monthly PSA was on a rising trend

• CT / Bone scan in 16 weeks – NED, PSA -8.0

• Patient was becoming anxious in spite of negative scans

What would you do to address this anxiety? ( in real life)

1) Get off trial and switch to another secondary hormonal therapy

2) Reassure patient with scans ( CT + bone scans)

3) If available ,do more sensitive scans ( MRI WB or PSMA PET) and act according to findings

Next

• After 32 weeks, bone scan revealed a L2 spinal met. He was asymptomatic . PSA had risen to 18.1

• Patient was taken off the trial

• He elected to use abiraterone acetate to which he responded to for nearly 1 year

• He subsequently progressed through abiraterone, docetaxel, enzalutamide and is currently on cabazitaxel

• In Feb 2018, when unblinding for PROSPER was done, not surprisingly he was noted to be on placebo arm

Summary

• nmCRPC is relatively uncommon presentation of CRPC

• Recent imaging techniques have to lead to stage migration ( PSMA PET)

• Data based on older imaging- ? Treating early mCRPC

• Clear mFS benefit with either Apa or Enza

• OS data not mature

• Can discuss with patients

THANK [email protected]

Members of the SingHealth GroupChangi General Hospital • KK Women’s and Children’s Hospital • Singapore General HospitalNational Cancer Centre Singapore • National Dental Centre Singapore • National Heart Centre Singapore • National Neuroscience Institute • Singapore National Eye Centre SingHealth Polyclinics

m0 crpc: where are we in 2018? · (3a) no recommenda tion maintain castrate serum levels of...

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