The oncologist perpesctive of treating de novo oligometastatic disease.

The oncologist perspective of treating de novo oligometastatic

disease.

Christopher Sweeney, MBBSMedical Oncologist, Dana Farber Cancer Institute

Professor, Harvard Medical School

Disclosures

Consultant with compensation

Research Funding

Amgen XAstellas X XBayer X X

Genentech/Roche XJanssen X XPfizer X

Celgene XSanofi X X

Dendreon XLilly X

Tolmar X

Spectrum of Prostate Cancer Tumor Burden: Prostate Gland Treated

Prostate Gland

Organ ConfinedLow Risk

Organ Confined - Risk of Mets

Rising PSA no mets

Metastatic Disease

CRPCRising PSA no/min metsEarly

Castration ResistantProstate Cancer: Later

Burden of Metastatic Disease

Oligometastatic hormone sensitive prostate cancer

Spectrum of Prostate Cancer Tumor Burden: Prostate Gland Intact

Prostate Gland

De Novo Metastatic Disease~ 9,000 pts in 2016 in USA1

Early CRPCRising PSA no/min mets

Castration ResistantProstate Cancer: Later

Oligometastatic hormone sensitive prostate cancer Management of the primary as well…

1 seer.cancer.gov; ~5% of 180,000 cases in 2016

What is oligometastatic prostate cancer?• Clinical trial groups have different definitions using conventional imaging CT

A/P and Tc bone scan to define low burden• Better OS / natural history with ADT alone

Low volume definitions

Visceral Disease Bone mets on Tc Bonescan

Nodal Disease

SWOG No Any number limited to vertebrae and pelvis

Yes

MDACC No 2 or less YesECOG No 3 or less or any number

if limited to vertebrae /pelvis

Yes

GETUG No Yes

Explaining the CHAARTED definition

• Explaining the CHAARTED definition: • Made use of sites and number of bone metastases to ensure patients

enrolled in first version were only high volume• Minimize misclassifying patients

• with oligometastatic disease (3 or less) even if one lesion was beyond vertebrae and pelvis

• SWOG: isolated rib met would be ‘extensive”• Degenerative changes in spine / pelvis read as cancer and falsely increase

number of mets• 4 areas of uptake in spine and pelvis – “Is it DJD or cancer?”• More likely higher burden of bone mets if vertebral mets and “spill” over to ribs,

long bones (qualifier)

Reproducibility of prognostic factors in GETUG15, CHAARTED and Hospital-based Registry at DFCI

Francini et al Prostate 2018; Gravis et al Eur Urol 2018

CHAARTEDGETUG15

Median OS(years)

PLT and LV ~8

PLT and HV 4.5

De Novo and LV 4.5

DeNovo and HV 3

St Gallens APCCC possible question

• Do you define oligometastatic disease as?• No visceral disease (lung or liver) and only 3 or less bone metastases• No visceral (lung or liver), no disease beyond the appendicular

skeletal involvement (SWOG definition)• Low volume disease per CHAARTED• Disease that can be encompassed by radiation ports and/or removed

by surgery (managed with local ablative therapies)

• Do we focus on the longer natural history or ability to ablate all “visible” disease to conventional imaging?

Gillessen et al 2015 Ann Oncol

Spectrum of Prostate Cancer - Tumor Burden

• Currently defined by Tc Bone Scan and CT A/P• Novel imaging

• PSMA based PET and gallium scanning• Choline PET imaging• Whole body MRI• NaF PET

• Will define more lesions / reveal lesions that were micrometastatic to conventional imaging

• Stage migration• Is biology of PSMA PET (+); Conventional Scan (-) indolent = dormant

• Conventional imaging with CT A/P and bone scan is boring, old school, gold standard … like a gold nugget from a stream … it has mud on it

• But ... If we had a serum blood test or new imaging that was as prognostic for OS as CT A/P and Tc bone scan • NEJM, Nature Paper• Press releases: “Biomarker heralds the future”

• Can ANYONE tell me the clinical significance of a patient with 2 bone metson bone scan but diffuse bone mets on PSMA PET positive?

• May have a role in guidance for SBRT for biochemical recurrence when conventional scan is negative

A Brief Word on PSMA PET Imaging

Why bother defining oligometastatic disease?

• For clinical trials to guide accurate risk stratification

• If the defined subgroup would be managed differently• Would matter if subgroups differed in outcome with a given therapy such as

ADT plus docetaxel

• Studied as unique entity

Treatment options for oligometastatic HSPC• ADT alone … approach for last 70 years• ADT plus abiraterone (or apalutamide press release)

- ? Value in low burden disease which maybe more AR dependent• Ablative therapy alone

• Metastases [plus prostate if prostate in place] • Goal: To delay ADT

• ADT plus local ablative therapy to all disease• Metastases [plus prostate if prostate in place]• Goal ? Curative intent because just a little further along from micromets

• ADT plus chemotherapy or abiraterone plus ablative therapy to all disease• Metastases [plus prostate if prostate in place]• Goal ? Curative intent or long interval off ADT on intermittent ADT

Oligometastatic disease and the primary

• Primary intact: manage the primary and systemic disease: • eg 55 yo PSA 50 ng/dL on screening and Gl8 on TRUS biopsy and 2

bone mets

• Primary removed and relapse years later• PSA rises to 5 at 8 years post RP and 2 bone mets noted and manage

systemic disease only

• Do these patients have a different biological behavior?

European Urol 2019 on line

For patients with 4 or less bone metastasis there was a 7% improvement in 3-year OS

Breaking news … randomized data

• STOMP trial (Ost et al JCO 2017)

• 62 pts with rising PSA after local therapy with curative intent

• 3 or less choline PET lesions• Surveillance or MDT (Surg/XRT)• Endpoint: ADT-free survival

• 13 months for surveillance• 21 months for MDT group

PLATON Study Schema: CCTG Study

Hormone sensitive oligometastatic prostate ca

408 patients < 5 metsSynchronous or metachronous

presentation

Randomized

1:1

Best systemic therapy:ADT

+/- abirateroneor docetaxel

Best systemic therapy:ADT

+/- abirateroneor docetaxel

+Local ablative therapy to all

sites of disease

Primary endpoint:Failure free survival

Secondary endpoints: Adverse events

Time to QoL deteriorationEconomical assessment

Overall survivalCancer specific survival

Correlative science

There will be 3 stratification variables:• Synchronous vs. metachronous presentation• Use of chemotherapy/2nd generation hormone therapy or not• Use of novel PET imaging or not

And now for what you have all been waiting for …

Definitive data on how to treat oligometastatic prostate cancer

And the answer is …

IME

IME

• “In my experience” is the level of evidence we have to work with given absence of randomized ph 3 data

• In area of uncertainty we are left with making the best decision based on patient factors and cancer features

“IME” Anecdote #1: de novo metastatic 66 yo in 2010 with left hip pain & sciatica and MRI pelvis bone

met -> PSA 1244 + Prostate mass. Tc bone scan uptake in left pubic bone only CT C/A/P craggy prostate; pubic bone lesion only Prostate biopsy: high volume Gleason 8

Treatment Dec 2010 ADT commenced Apr 2011 radiation to bone met and prostate ADT completed Jan 2013.

Surveillance off ADT: June 2014: PSA 0.05 with test of 340. Mar 2019: 0.05 ng/mL; testo 190 ng/dL 73 yo working full time

“IME” Anecdote #2: Post prostatectomy

Jan 2014 67 yo Haitian of African ancestry PSA of 4.8 Gleason 3+4=7 in 3 of 12 cores Apr 2014: Prostatectomy: Gleason 4+3=7 (minor pattern 5) and

focal extraprostatic soft tissue Post-op PSA 2.4 Tc bone scan and MRI: left femoral neck met

Treatment ADT Jun 19, 2014 until Jun 2016 RT to bone lesion finished 9/26/14 Feb 2019: PSA 0.01 ng/mL , testo 350

Now 72 yo, ++ exercise, mild incontinence

“IME” Anecdote #3: Intermittent ADT1998: PSA 7.0 and biopsy Gleason 3 + 3 = 6 in 1 of 10 cores and treated with

partial brachytherapy PSA nadir of ~ 2.5 PSA: 2004 = PSA 4.7 / 2010 = 8.6 / May 2010 = 17.2 with deep buttock

discomfort at age of 73 yoTc bone scan - intense uptake in the left and right ischium

Treatment: Intermittent ADTJune 2010 ADT with PSA decline from 23 to to 0.02 4 courses of 12 monthly treatments and breaks of about 12 months (Feels

better off and recovers testosterone)82 yo in Mar 2019: PSA 2 ng/mL and testo <7 ng/dL after 6 months

leuprolide and poor urine output repeat imaging: no bone mets but local recurrence: referred for salvage

brachy vs cryotherapy as local recurrence morbidity

IME Anecdote #5: Early progression

July 2012 PSA 1.7 and 10.9 at age of 64 yo July 10, 2013: TRUS biopsy Gleason 9 and CT scan: bone scan T11 only: MRI sclerotic focus in the

vertebral body with extension into the right pedicle October 3, 2013: prostatectomy with 1.5cm Gleason 9 and focus of extracapsular

extension. Seven lymph nodes negative.

October 2013: seen at DFCI PSA 0.09, incontinent SRS to T11 met Sept 2014: CT for stones showed multiple new small sclerotic bone: “flare” Feb 2015 - PSA 0.05 and December 2015: PSA 0.19, casodex dc‘d April 2016, PSA 0.48, bone scan: decrease at T11. Incontinence resolved, working as carpenter at 67 yo Dec 2016: PSA 2.5 added enzalutamide Mar 2019: PSA 0.8

Did the local Rx to bone met and primary delay clinical progression / increase longevity?

Aug 2013

Sept 2014

Inconclusive conclusion #1• It is tempting to think we can cure some patients with oligometastatic

disease• If very AR dependent with AR directed therapy

• and clinical trials augmenting AR inhibition are ongoing (STAMPEDE-abi, TITAN, ENZAMET, ARCHES)

• It is next part of the spectrum where we cure some patients with high risk localized prostate cancer with micromets occult to conventional imaging with ADT added to XRT

Inconclusive conclusion #2• It is tempting to think we can increase the chance of cure of some patients

with oligometastatic disease• By augmenting therapy with non-AR directed therapy• Local ablative therapies (radiation or surgery) added to ADT if treatment burden of

local ablative therapy is reasonable

Very Inconclusive Thought

• My preference is to use ablative local therapies to all disease with the least treatment burden plus ADT for 2 years without docetaxeland stop ADT if PSA < 0.2 and see degree of control

• And enroll on a trial (e.g. STAMPEDE, Canadian) of ADT + MTT• Increase chance die of something else without burden of relapse or burden of

further therapy (this is the optimistic / proactive approach)?• Some maybe cured / die with low PSA and recovered testosterone

• What is upper limit of SRS?• Manage primary if intact: Surgery vs EBRT vs HDR brachytherapy?