Current Concepts in Extending

Systemic and Local Therapies to

Maximize Prostate Cancer Control

Tanya Dorff, MD

DISCLOSURE

• Grant/Research Support from Bayer

• Consultant for Bayer, EMD Serono and Janssen

• On the Speakers Bureau for Exelixis and

Prometheus

Overview

• Localized disease: multidisciplinary management

– Includes genetic counseling

• Metastatic hormone sensitive (mHSPC): intensified up-

front therapy extends survival

– Abiraterone, docetaxel… maybe more to follow

• Novel therapies for metastatic castration-resistant prostate

cancer (mCRPC)

– Optimizing use of existing therapies

– Genomic targeted therapies (PARP, pi3k…)

– Immunotherapy

Staging: NCCN 3/2018

The Case for Adjuvant ADT

for high risk localized

• ECOG (Messing) trial in

LN+ showed significant

benefit to immediate ADT

• SWOG 9921 trial showed

benefit in LN+ as well as

other high risk groups with

2 years adjuvant ADT

Dorff TB et al JCO 2011; 29:2040

Messing EM et al. NEJM 1999;

341:1781

The case for Adjuvant radiation therapy for high risk

localized prostate cancer

• For T3 patients, adjuvant radiation reduced risk of

metastasis at 10 years

– Decreased use of ADT at 5 years: 21% on observation

vs 10% on XRT arm HR 0.45 (0.29-0.68)

Thompson et al JAMA

2006; 296:2329

In LN+ should we use both ADT + XRT?

• Retrospective analysis, suggests patients with 4+ nodes

may not benefit from adjuvant Radiation

Abdollah F et al J Clin Oncol 2014;

32:doi/10.1200/JCO.2013.54.7893

Decipher: Select patients for Radiation Post RP?

• “Genomic Classifier Identifies Men With Adverse Pathology After

Radical Prostatectomy Who Benefit From Adjuvant Radiation Therapy”

Den., et al.,J Clin Oncol, 2015, 33:944-951.

Ross AE et al. PCAN 2014; 17:64-9

Low risk (GC<0.4) High risk (GC≥0.4)

• Prostatectomy

• 22 gene panel RNA selected from patients with recurrence

• PRIMARY USE: select adjuvant therapy after prostatectomy

Salvage

Adjuvant

Future: clinical trials in localized prostate cancer

Setting Agent(s) Accrual

goal

Status

ENZART

NCT03196388

Intermed Risk Enzalutamide

HypoFx XRT

70 Recruiting

DFCI

NCT02028988

Intermed Risk Enzalutamide

EBXRT

64 Completed

ENZARAD

NCT02446444

High Risk

No LNs x pelvis

ADT + XRT

Enza vs Bical

802 Ongoing

EORTC

NCT03488810

Intermed, limited

hi risk

ADT + XRT

+/- Apalutamide

990 Opening soon

Genetic Testing

BRCA 1 & 2 mutations are

more common in prostate

cancer than previously

thought

- Pritchard et al NEJM 2016

Only 20% of a panel of experts felt genetic testing should

be done in a majority of advanced prostate cancer patients

- 93% supported testing in men with + family history

- 74% supported testing in men dx prostate CA < 60 years

Gilessen S et al Eur Urol 2018; 73:178

ADT: managing side effects

• Hot flashes (gabapentin1, venlafaxine2)

• Metabolic syndrome: Diet/Exercise, metformin3, statins

• Cognitive changes (focus/attention): methylphenidate

• Emotional changes: SSRI

• Bone mineral density: Bisphosphonates or denosumab

60 mg SQ q6 months4

– Resistance and Aerobic Exercise can improve muscle

mass, physical function

– Toremifene also helpful5,6

1. Loprinzi C et al. Ann Oncol 2009; 20:542 2. Irani J et al. Lancet Oncol 2010; 11:147

3. Nobes JP et al BJU Int 2012; 109:1495 4. Smith MR et al. NEJM 2009; 361:745

5. Smith MR et al. JCO 2008; 26:1824 6. Smith MR et al. J Urol 2008; 179:15

Early chemotherapy improved survival in metastatic hormone

sensitive prostate cancer (HSPC): CHAARTED

ESMO update: med f/u 57 mo, no OS

benefit for low volume (aka oligomets) Sweeney CJ et al, ESMO 2016; abstr 720pd

Sweeney CJ et al. NEJM 2015;

373:737-46

STAMPEDE: (Docetaxel) in mHSPC James N et al., Lancet 2016; 387:1163

For Overall Survival: BUT…

HR 0.79, 95% CI 0.65-0.96, p=0.019 – all patients Toxicity must be considered

HR 0.82, 95% CI 0.48-1.4, p=0.475 – pts with mets

Early abiraterone improves survival in

metastatic HSPC: LATITUDE

Fizazi K et al. NEJM 2017;

DOI:10.1056/NEJMoa1704174

2 of 3 high risk features:

- Gleason 8-10

- 2+ bone metastases

- Visceral metastases

STAMPEDE: up-front abiraterone James N et al, NEJM 2017 DOI10.1056/NEJMoa1702900

Hi risk local or Node+ Relapsing p definitive tx

≥2 of: Stage T3/4 >1 of: PSA >4 & PSADT <6 mo

PSA≥40ng/ml PSA >20

Gleason 8-10 Mets or Node +

No difference between

abiraterone and

docetaxel for mHSPC

Sydes MR et al. Ann

Oncol 2018; 29:1235-48

https://doi.org/10.1093/an

nonc/mdy072

Trials will answer the combination and other agents’

utility for mHSPC intensification questions

Study Agent(s) Accrual Goal Status

ARASENS (Bayer)

NCT02799602

Docetaxel

ADT

+/- ODM-201

1300 Completed Accrual

SWOG S1216 ADT +/- orteronel

(TAK700)

1313 Completed Accrual

TITAN

NCT02489318

ADT +/- apalutamide 1052 Completed Accrual

ARCHES

NCT02677896

ADT +/- enzalutamide 1150 Ongoing

STAMPEDE ADT + abiraterone +/-

enzalutamide

? Ongoing

Next generation questions: - Which drug for which patient?

- Shorter duration?

Optimizing use of existing therapies:

Ensure Drug Is No Longer Working Before Stopping

•Scher HI, et al. J Clin Oncol. 2011;29:3685-3704.

23

25

A Drifter for

3.5 YEARS

0

PS

A,

ng

/mL

5

2

Time, months

7

6

4

3

1

Treatment Start

Symptomatic Progression (bone)

Palliative

Radiation

Imaging Time Points

BL

Scre

en

#3

Scre

en

#2

Scre

en

#1

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Sequencing: less effect of abi after enza, and enza after abi

• Abiraterone response after

prior treatment with

enzalutamide1

• Enzalutamide versus

docetaxel in men with CRPC

progressing after abi2

1. Loriot Y, et al. Ann Oncol 2013;24:1807-1812. 2. Suzman DL, et al. Prostate. 2014; 74:1278-1285.

ARV7 Predicts Less Response to

Enzalutamide and Abiraterone

Antonarakis et al, NEJM 2014. ARV7 explains some of the

cross-resistance

But response to Docetaxel

is not impacted by ARv7

Antonarakis et al, 2015.

PLATO: Should we continue AR targeted therapy

through subsequent lines of tx, similar to LHRH?

Presented by: G.

Attard, ASCO 2016.

NCT01995513

Using and sequencing cabazitaxel

• FIRSTANA: cabazi vs doce 1st mCRPC: No difference1

• Cabazi 20 mg/m2 vs 25mg/m2: No difference in OS2

• Retrospective series: Doce-Cabazi-Abi better than

• Doce-Abi-Cabazi3

1.Oudard et al. JCO 2017;

35:3189 (FIRSTANA)

2. Eisenberger et al. JCO

2017; 35:3198 (PROSELICA)

3. Sonpavde et al. CGUC

2015; 13:309

Novel agents: Pi3K/AKT targeted tx (for PTEN loss)

• PTEN loss

present in up to

60% of prostate

cancer

• Cross-talk with

AR

• Ipatasertib is

AKT inhibitor

Novel agents: PARP

Inhibitors (for DDR)

Pritchard et al, 2016 (right)

Mateo et al, NEJM 2015 (below)

Theranostics: individualize treatment plans based on

phenotype rather than genomics

Not all mCRPC tumors are PSMA +

Treatment with Lu177-PSMA 617

Emmett L et al. J Med Rad Sci 2017; 64:52

Pre-treatment Post-treatment

Novel agents: Epigenetic modification

BET bromodomain

inhibitors, EZH2

inhibitors in early

phase clinical trials

Immunotherapy

has established

value in mCRPC

(but there have been

multiple negative

phase 3 trials)

Schellhammer PF et al

Urology 2013; 81:1297

No benefit for PROSTVAC in phase III

J. Gulley (NCI) ASCO 2018

Drake C et al. Urology

2013; 81:381

Objective responses are

uncommon with Sip-T,

but can occur

A. May 2010 – before SipT

B. Oct 2012 – post SipT,

with T recovery

Dorff TB et al. Clinical GU

Cancer 2014; 12:e55

Pembrolizumab in mCRPC: KEYNOTE-199

Top right: objective

response

Bottom right:

PSA changes

DeBono JS. ASCO

2018; oral present

Ongoing immunotherapy trials

Agents Trial # Accrual goal Locations

Sip T +/-

Radium223

NCT02463799 34 Cedars Sinai

Hopkins

Radium223 +/-

pembrolizumab

NCT03093428 45 Dana Farber

SipT + immed vs

delayed ipi

NCT01804465 54 UCSF

MDACC

Enza +/-

atezolizumab

NCT03024216 730 US sites closed to

accrual

SipT +

atezolizumab

NCT03024216 34 City of Hope

U Hawaii

Chimeric Antigen Receptor

(CAR) T Cell-Based Therapy

Adapted from Roberts et al, Leuk & Lymphoma 2017.

Escape mechanisms in most cancers

MHC down-regulation / defective

antigen presentation of TAAs

Immunosuppressive tumor-infiltrating

immune cells

Advantages over other immunotherapy strategies:

1. Direct attacking of tumor-associated antigens

2. MHC-independent

3. Less opportunity for immune escape

Conventional TCR:MHC Chimeric antigen receptor

Gtex

PSCA

PSMA

TCGA

PSA (KLK3)

PSMA

PSCA

Normal tissue expression Tumor tissue expression

PSCA as a prostate cancer CAR target

A Phase I clinical trial to evaluate PSCA-CAR T cells for the

treatment of patients with mCRPC

! 4

Toxicity and disease response evaluations will be evaluated as described above.

Study Population: Patients eligible for the proposed study should have 1) pathologic diagnosis of prostate cancer, (2) metastatic castration resistant prostate cancer (mCRPC) (Note: castration will be defined by a

testosterone <50 ng/dL achieved by orchiectomy or LHRH agonist/antagonist therapy), 3) disease progression

on the last line of therapy based on: rising PSA with 2 consecutive values 7 days apart or measurable disease

with an increase in 20% or more of longest diameters of measurable lesions or non-measurable disease with 1 or more new lesions in soft tissue, or 2 or more new lesions in bone, and (4) prior abiraterone or enzalutamide,

but not both. Patients may also have had 1) chemotherapy for castration-sensitive prostate cancer, but not for

castration-resistant disease, 2) prior radiotherapy, provided it was rendered > 28 days prior to treatment, or 3) prior use of sipuleucel-T.

Objectives: The primary objectives are 1) to evaluate the safety and tolerability of PSCA(ΔCH2)BBζ-CAR T

cells in patients with mCRPC, and 2) identify the recommended Phase II dose (RP2D). The secondary

objectives are 1) to assess clinical response based on Prostate Cancer Working Group 3 (PCWG3) criteria and 2) to assess whether PSCA-CAR T cells expand and persist. Correlative objectives include 1) enumeration and

phenotypic characterization of circulating tumor cells (CTC) pre- and post-therapy and 2) characterization of

humoral and cell-mediated immunity to PSCA and other known prostate cancer antigens.

Endpoints: The primary endpoints are DLTs and all other toxicities post CAR T cells. The secondary endpoints

include: 1) response based on Prostate Cancer Working Group 3 (PCWG3) criteria and 2) persistence of T

cells to 28 days post infusion (defined as CAR T cells >0.1% of total CD3 cells by flow-cytometry; AUC of log10 copies/µg of genomic DNA). The correlative endpoints are 1) assessment of circulating tumor cell (CTC)

conversion (from ≥5 CTCs/7.5 mL to <5 CTCs/7.5 mL, or vice versa) and 2) detection of AR-V7 splice variants.

Toxicity: will be assessed using the National Cancer Institute’s Common Terminology Criteria for Adverse

Events (CTCAE v5). A DLT is defined as: 1) any Grade 3 or higher toxicity occurring within 28 days of T cell infusion with an attribution of definitely or probably related to T cell infusion, excepting expected adverse

events of specified grade and duration, including cytokine release syndrome (CRS); and 2) any Grade 3 or

greater autoimmune toxicity occurring within 28 days of T cell infusion. A toxicity of any grade that is normally expected with advanced prostate cancer or related prior therapy and/or treatment will not be considered a DLT

with respect to protocol continuation, or dose escalation/de-escalation of T cell dose.

Study Design: This is a Phase I dose escalation trial of adoptive T cell therapy. This trial seeks to determine an RP2D to test in future phase II

trials. RP2D will be based on maximum tolerated dose (MTD),

participant data on disease response, late toxicities and 2nd infusions.

The toxicity equivalence range (TEQR) design of Blanchard and Longmate22 will be used to evaluate select doses of PSCA(ΔCH2)BBζ-CAR T cells and determine the MTD.

The dose schedule is shown in Table 1. The starting dose will be dose 0. The TEQR design22 can be viewed

as a minimal elaboration of the 3+3 design to include an explicit toxicity target range, and permit intuitive specification of a too-toxic level for closing a dose level. In this implementation of the TEQR design, we define

the target equivalence range of DLT as 0.20-0.35. Toxicity levels of 0.51 or higher will be considered too toxic

Table 1. CAR+ Cell Dose Schedule

Dose -1 Starting Dose 0

Dose 1 Dose 2

25M 50M 200M 800M

Figure 3: T cell product manufacturing and patient treatment plan. BX = biopsy, PB = peripheral blood for correlative assays, CT =!computed tomography scan, PET = positron emission tomography, LTFU = long-term follow-up. *Cyclophosphamide lymphodepleting regimen, 1 or 2 days at the discretion of PI, based on disease burden and co-morbidities. **T cell infusion may be given within a window of 3-10 days after last dose of lymphodepleting regimen

Bx = biopsy

Cy* = lymphodepletion chemotherapy, cytoxan +/- fludarabine

PB = peripheral blood for correlative studies

LTFU = long term follow up

Enrollment: min 6, max 27; goal 12 at MTD/RP2D

Inpatient approx days 0-14

Conclusions

• Genetic counseling

• Consider ADT adjuvant for high risk in addition to

XRT

• Supportive care key for long-term ADT patients

• Continue enza, abi beyond PSA progression

– but not when ready for new therapy

• PARP inhibitors completing phase 3 testing

– genomic profiling relevant

• Immunotherapy still a work in progress