Adjuvant Therapy in High-Risk Prostate Cancer after ... 7 Talk 4... · Adjuvant Therapy in High-Risk Prostate Cancer after Radical Prostatectomy. Conflict of Interest Statement Structured

Robert Bristow MD PhD FRCPC Clinician-Scientist and Professor,

Radiation Oncology and Medical Biophysics,

Princess Margaret Cancer Center & University of Toronto

Lead Investigator, Canadian Prostate Cancer

Gene Sequencing Network (CPC-GENE)

Adjuvant Therapy in High-Risk Prostate Cancer

after Radical Prostatectomy

Conflict of Interest Statement

Structured Research Agreements:

• GenomeDx

• AstraZeneca

1. Use of Adjuvant RT 2. Use of Adjuvant Chemo-hormonal therapy 3. Future Trials and Biomarkers

Content Outline

Surgical Outcomes

MSKCC: 1,389 surgical patients with cT1-3 CaP

Positive surgical margin identified in

• 6.8% with pT2

• 23% with ECE (pT3).

10-yr independent predictors of progression free survival on MVA:

Positive surgical margin (10-year PFP: 58% vs 81%)

Pre-operative PSA

Gleason score

Extra-capsular extension

SV invasion

Nodal positivity Swindle, Scardino et al J Urol 2005

Intraductal Carcinoma-Cribiform Architecture

Kweldam, Mod Path; 2015

Taylor, Nat Comm; 2017

1031 biopsies in ERSPC: IDC-CA was an independent

predictor for distant metastasis-free survival (HR 8.0, 95%

CI 3.0–21; P<0.001) and disease-specific survival (HR 5.4,

95% CI 2.0–15, P=0.001).

Clonal

Adjuvant RT Concepts

• PSA screening leasing to increased use of active surveillance (AS) and therefore

increased aggression in patients subsequently undergoing radical prostatectomy

(RadP)

• At least 30% of men will have high-risk post-operative factors, post-RadP

– Extracapsular extension (ECE), margin positivity, SV invasion, increased

Gleason score, IDC-CA and lymph node positivity (N+)

• The majority of men with biochemical relapse following RadP will have positive

molecular imaging in the prostatic fossa or the pelvis if left untreated

• Local component to pattern of failure: anastamosis, pelvic lymph nodes.

• Risk of systemic failure in high-risk individuals. • Potential role for additional local therapy.

• Potential role for systemic adjuvant therapy for high-risk individuals.

3 Randomized Trials: Adjuvant RT Following Surgery

Gandaglia et al; Eur Urol; 2017

Randomized Trials: Adjuvant RT Following Surgery

Gandaglia et al; Eur Urol; 2017

SWOG 8794

Thompson J Urol 2009

P= 0.023

10-year OS: 74% versus 66%

(NT 1/10)

Bolla et al Lancet 2012

10-year bPFS: 60.6% v 41.1% (NT 5)

10-year OS: 76.9% v 80.7% (nss)

EORTC 22911

Wiegel et al JCO 2009

All patients-intent to treat

ARO 96-02

5-year loco-regional failure:

5.4% v 15.4%

EORTC 22911

Bolla et al Lancet 2005

10-year PFS: 56% vs 35%

(NT 5)

Randomized Trials: Adjuvant RT Following Surgery

Gandaglia et al; Eur Urol; 2017

Meta-Analysis (Daly et al., 2011) of all three trials: improved OS and decreased metastases EORTC/SWOG subset analysis for best responders: positive margins, GS 8-10, LN+, SV+

Lin JNCI 2015

National Cancer Database:

Propensity-matched N+

Figure 2. Failure-Free Survival for Reported Radical Radiotherapy Status, in N0M0 and N+M0 Subcohorts

James et al. Page 15

JAMA Oncol. Author manuscript; available in PMC 2016 March 14.

Europe PM

C Funders A

uthor Manuscripts

Europe PM

C Funders A

uthor Manuscripts

STAMPEDE (M0): N+ vs N- Disease

James et al.,

JAMA Oncology 2016

Gandaglia et al;

Eur Urol; 2017

Retrospective Studies: Adjuvant RT in N+ Patients

Majority of studies support suggest benefit of aRT in Node + patients presumable to optimize local control (PLND and ePLND may both benefit)

Adjuvant vs Salvage RT • Prospective randomized trials support a role for aRT in reducing the risk of biochemical

• recurrence (BCR) by 20-30% and improved MF and OS.

• Majority of retrospective studies support aRT over sRT (e.g. 10 year rates of metastasis and

BF decreased by aRt over sRT); although many biases (Gandaglia et al; Eur Urol; 2017)

• However, 40% of patients or more managed with initial observation will not recur at 10-yr follow-

up

• Issues with adjuvant RT: over-treatment (40% will not fail at 10 years), associated side-effects

(acute: 15-30%; chronic: 2-8%; meta-analysis shows increased GI tox, strictures, incontiennce,

but not erections; Daly, 2011)), patient inconvenience, health care resources

• Consequently, aRT is administered in approximately 20% of contemporary patients versus sRT

despite lack of Level I evidence; bolstered in era of ultra-sensitive PSA testing

Decision for Post-OP RT Adjuvant or salvage +/-

ADT ?

RADICALS MRC/NCIC-CTG

RANDOMIZE

RT Alone RT + 6 mo ADT

RT + 2 years ADT

Uncertainty about need for Post-Op RT

(High Risk Features)

RANDOMIZE

Immediate RT (within 6 mo)

Early salvage RT (PSA < 0.4)

N= 1350, 2800

Primary endpoint: disease specific survival

RAVES TROG

pT3 or margin positive or SV positive

RANDOMIZE

Immediate RT (within 6 mo)

Early salvage RT

N=470

Primary endpoint: non-inferior to treatment for biochemical failure

Gandaglia et al; Eur Urol; 2017

Prospective Trials: Adjuvant vs Salvage RT

Presented By L. Glode at 2017 Genitourinary Cancers Symposium

Adjuvant ChemoHormonal Therapy SWOG S9921: ADT versus ADT + Mitoxantrone +Prednisone

Presented By Susan Slovin at 2017 Genitourinary Cancers Symposium

TAX-3501 VA Cooperative Study #553

CONCLUSION: Trials failed to accrue and underpowered for their primary endpoints; No hint as to benefit; possible subset in PT3b/African Americans in VA-553 (hypothesis)

ADT- DOC-ESTRA

vs ADT: GETUG 12

Delayed vs Immediate

ADT: N+ (EST 338)

Messing, Lancet Oncol, 2006

p=0·04

Fizazi, Lancet Oncol, 2015

8-year relapse-free survival: 62% versus 50%; [HR] 0·71, p=0·017

RTOG 0521: ADT+DOC +RT vs RT+ADT

Sandler, ASCO, 2015

In the study, the 4-year OS rates were 89% for men who received ADT and RT versus 93% for men treated with ADT, RT, and docetaxel (HR = 0.70; 90% CI, 0.51-0.98; P = .04)

6 | ADVANCE ONLINE PUBLICATION www.nature.com/ nrurol

compared with 6% of DTC-negative patients,17 implying

that a large proportion of DTC-positive patients do not

develop widespread metastatic disease and suggesting

that many of the marrow-associated prostate cancer cells,

if they do have metastatic capacity, remain clinically and

biologically dormant.48

CTCs might also represent an important biomarker

of occult metastases, as concordance has been observed

between the presence of CTCs in blood and DTCs in

bone marrow in patients harbouring tumours defined as

Gleason ≥8.49 Indeed, patients with metastatic castration-

resistant prostate cancer (mCRPC) have significantly

increased levels of CTCs relative to patients with local-

ized high-risk disease.50 The number of CTCs predict the

magnitude and duration of PSA response in patients pre-

senting with de novo metastatic prostate cancer and ADT

is used as the initial primary treatment in these men.51

Furthermore, CTCs are also prognostic for overall sur-

vival in patients with mCRPC receiving chemotherapy.52

Unfortunately, there are few data that support the use of

CTCs to predict metastatic potential in aggressive, high-

risk or locally advanced prostate cancer to justify the use

or nonuse of ADT with IGRT.53 Similarly, the use of a

blood-associated ‘liquid biopsy’ for circulating tumour

DNA (ctDNA) or RNA (ctRNA) as a biomarker for

occult metastases in the localized disease setting requires

extensive study and validation before it can influence

clinical management.52,54

Future developments in the area of molecular imaging

could also help to better define patients with occult

metastasis at diagnosis who might benefit from com-

bined ADT–IGRT. Novel MRI strategies using ultrasmall,

superparamagnetic particles of iron oxide could improve

detection of first echelon metastases within pelvic lymph

nodes during staging in patients with prostate cancer. This

capacity would enable the use of appropriate IGRT treat-

ment volumes (for example, treating the prostate alone or

adding a pelvic field) and also provide a means of select-

ing patients with node-positive disease for participation

in novel clinical trials to improve survival.55 Whole-body

MRI, including diffusion-weighted imaging, is being

actively investigated to improve the detection and dis-

crimination of synchronous micrometastases or provide

evidence for limited oligometastatic sites that could be

ablated with SBRT with curative intent.56 Novel PET

tracers for detecting early or lytic bony metastasis might

have additional utility for both initial staging and monitor-

ing of response to systemic therapy.57,58 PET tracers such

as 18F-choline or 11C-choline can be used to detect lymph

node involvement in patients with localized prostate

cancer with a pooled sensitivity of 49.2% (95% CI 39.9–

58.4%) and pooled specificity of 95% (95% CI 92–97.1%),59

and can predict PCSS in patients experiencing biochemi-

cal failure during ADT.60 Novel PET tracers for use in the

setting of prostate cancer include 18F-fluciclovine, which

targets leucine metabolism,61 68Ga-PSMA-ligand,

which targets prostate-specific membrane antigen,62 bom-

besin, which targets the gastrin-releasing peptide recep-

tor (GRPR)63 and 16β-18F-fluoro-5α-dihydrotestosterone

(FDHT).64 Use of these tracers could improve the detec-

tion of extraprostatic metastases at initial diagnosis and

enabling the efficacy of systemic ADT or molecular

t argeted therapies to be tracked.

Importantly, in the era of molecular genomics, several

prognostic signatures based on genome-wide analyses

of RNA and DNA are being studied to assist in decision-

making regarding the use of adjuvant IGRT and/or ADT

after radical prostatectomy.65–72 Future advances in the area

of prognostic genomics could include the development of

a gene signature that could enable clinicians to assign

patients to treatment escalation (for example increas-

ing the dose of IGRT that patients receive or a adding

systemic therapy such as ADT) or de-escalation (with

no requirement for systemic therapy) protocols on the

basis of diagnostic biopsy, thus providing a priori infor-

mation regarding a patient’s likelihood of experiencing

treatment failure.73 The use of these invasive and/or non-

invasive assays might help to better define the fraction of

patients harbouring occult metastases whom could benefit

from combined ADT–IGRT and improve their survival

o utcomes (Box 2).

Cancer metabolism and hypoxia have been linked

to differential androgen signalling and radiotherapy

response. Ranasinghe et al.74 demonstrated that patients

whose tumours express HIF1-α (hypoxia-inducible

factor 1α) have significantly decreased metastasis-free

survival compared with patients with no HIF1-α tumour

expression. On multivariate analysis, HIF1-α expression

was an independent risk factor for metastasis (HR = 9.8,

P = 0.017). Furthermore, nonspecific HIF1-α inhibitors

seem to increase PFS and reduce the risk of developing

metastases in patients receiving ADT.75 These observa-

tions indicate that HIF1-α could be a marker of disease

progression. Al-Ubaidi et al.76 demonstrated that down-

regulation of HIF1-α occurred after castration in five

out of 14 patients with high-risk, locally advanced pros-

tate cancer, all 14 of whom had strong HIF1-α expres-

sion before castration. Yapp et al.77 utilized the Shionogi

tumour model to demonstrate, using flow cytometry

and PET imaging with a radiolabelled tracer for hypoxia

(18F-EF5), significantly higher levels of hypoxia in CRPC

Box 2 | Potential biomarkers for residual or recurrent prostate cancer or metastasis

■ Disseminated tumour cells

■ Circulating tumour cells

■ Intratumoural hypoxia78

■ Molecular imaging

■ Whole-body MRI

■ PET

Genomic (DNA, RNA) signatures

■ Cell-cycle progression score (Prolaris® test [Myriad Genetics, USA])

■ Oncotype Dx® test (Genomic Health, USA)

■ Decipher® test (GenomeDx, USA)

■ Prostarix™ test (Metabolon, USA)

■ Signature of genes regulated by NF-κB

■ PGA100

Selected genes, based on copy number alteration, RNA or protein expression

■ TP53, MDM2, MYC, NKX3-1, NBN, PTEN, SCHLAP199

Abbreviations: NF-KB, nuclear factor κ-light-chain-enhancer of activated B cells; PGA, percent

genome alteration.

REVIEWS

© 2015 Macmillan Publishers Limited. All rights reserved

Adjuvant Biomarkers for RT-ADT-CHEMO Treatment

Locke, Dal Pra, Bristow; Nat Rev Urol; 2015

High PORTOS Low PORTOS

High PORTOS group (1/4 patients): 4% in the radiotherapy group vs 35% in the no radiotherapy group; HR 0·15 [95% CI 0·04–0·60], p=0·0020; Low PORTOS group: 32% in both Caveat: PSA kinetics/Margin status missing; variable RT and ADT and only 12% patients received aRT

Needs validation

“PORTOS: 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched,

retrospective analysis” (Zhao et al; Lancet Oncology, 2016)

PORTOS and DECIPHER SIGNATURES

• Post-operative RT is a valuable adjunct to surgery and well-tolerated

• Optimal timing of adjuvant RT and role of ADT not yet established [cf. sRT (GETUG-

AFU-16 (6 months) vs. RTOG 9601 (2 years)]

• Need to optimize RT dose/volume/delivery/nodal technique to maximize control and

minimize RT-related toxicity; IGRT 60-66 Gy

• No published data supporting general use of Adj. chemo-ADT and OS;

– Possible subsets of patients who benefit (pT3/T4; African American, high PSA)

– Needs further trials and longer follow-up in GETUG and NRG/RTOG trials

• In my own practice with high-risk patients:

– Enroll in multimodal clinical trials (PUNCH-CALGB 90203)

– If aRT: 50/25Gy to pelvis (if no ePLND) and 66/33 Gy to prostate in margin-positive,

N+ or IDC-CA+

– 6-24 months of adjuvant ADT depending on reassessment-tolerance

Summary

• Neoadjuvant chemohormonal therapy; mostly Phase II trials

– Silberstein, JCO, 2014: Paclitaxel, Carboplatin, Estramustine-no difference in outcome when

compared to RadP comparator group

– Taplin, JCO, 2014: Abi plus LHRH to effectively suppress T; very few pT0/MRD

– Montgomery, CCR, 2016: Enza +/- LHRH/DUT; only 4/48 achieved MRD, pT0

– Note neoadjuvant chemohormonal therapy-treated FFPE biopsies can yield information AR status and NE/EMT genes to identify molecular outliers (Beltran et al., JCO, 2017)

• Increasing use of genomics and imaging will re-define sub-groups

– Use of genomic assays: DECIPHER, PORTOS, Germline DNA repair

– Molecular imaging (PET; wbMRI) to rule out metastatic disease in clinically-staged patients

• Need to support ongoing RCT’s to answer outstanding questions using modern

molecular imaging, genomics, and state-of-the-art androgen deprivation and blockade

(ABI/ENZA)

Summary-Future