Appraisal of Recent Progress in Metastatic Castration-Resistant Prostate Cancer

Appraisal of Recent Progress in Metastatic

Castration-Resistant Prostate Cancer

Oliver Sartor, MD

Laborde Professor of Cancer Research

Medical Director, Tulane Cancer Center

Departments of Medicine and Urology

Assistant Dean for Oncology

Tulane Medical School

New Orleans, Louisiana

Disclosures

Dr. Sartor discloses the following commercial

relationships:

Consultant: AstraZeneca, Bayer, Bellicum, Bristol-Myers

Squibb, Celgene, Dendreon, EMD Serono, Johnson & Johnson,

Oncogenex, Pfizer, Sanofi-Aventis, and Tokai

Grants/research support: from Bayer, Endocyte, Innocrin,

Johnson & Johnson, and Sanofi-Aventis

Learning Objectives

Assess predictive and prognostic markers to refine

treatment planning for individual patients with

metastatic CRPC

Discuss the implications of drug resistance in

treatment selection for patients with metastatic

CRPC

Evaluate efficacy and safety data on novel

therapeutic regimens for metastatic CRPC

CRPC = castration-resistant prostate cancer.

Recurrent After Initial Hormonal Therapy

Deaths: 26,730

Radiographic

Metastases:

Castrate

1st-line

chemo

Docetaxel

Radiographic

Metastases:

Castrate

Post-chemo

Cabazitaxel

Abiraterone

Enzalutamide

Radium-223

Prostate Cancer Clinical States

PSA = prostate-specific antigen; ADT = androgen deprivation therapy.

NCCN, 2017.

Hormone Sensitive

Diagnoses: 161,360

Rising PSA

Salvage Rx,

ADT,

or no therapy

Localized

Disease

Local therapy

or no therapy

Rising PSA:

Castrate

No standard

of care

Overt

Metastases

ADT +

Docetaxel or

abirateroneFirs

t

Metastatic CRPC

Radiographic

Metastases:

Castrate

Pre-chemo

Sipuleucel-T

Abiraterone

Enzalutamide

Radium-223

Inherited DNA-Repair Gene Mutations

in Men With Metastatic PC

11.8% of men with metastatic prostate cancerBRCA2: 5.4%

CHEK2: 1.9%

ATM: 1.6%

BRCA1: 0.9%

RAD51D and PALB2: 0.4% each

4.6% of men with localized prostate cancer

PC = prostate cancer.

Pritchard et al, 2016.

Why Are Germline Mutations

Important?

Poor prognosis and early age of onset

Implications for future therapiesToday, PARP inhibitors, platinum agents, and PD1 inhibitors

Tomorrow, perhaps others

Implications for family members that may require careful

monitoring or even prophylactic surgery~70% of women with a BRCA2 pathologic mutation develop breast

cancer, ~40% for ovarian cancer

Pritchard et al, 2016; Mersch et al, 2015.

Prostate Cancer Clinical States

NCCN, 2017.

Recurrent After Initial Hormonal TherapyHormone Sensitive

Diagnoses: 161,360 Deaths: 26,730

Rising PSA

Salvage Rx,

ADT,

or no therapy

Radiographic

Metastases:

Castrate

1st-Line

Chemo

Docetaxel

Localized

Disease

Local therapy

or no therapy

Rising PSA:

Castrate

No standard

of care

Overt

Metastases

ADT +

Docetaxel or

Abiraterone

Radiographic

Metastases:

Castrate

Post-chemo

Cabazitaxel

Abiraterone

Enzalutamide

Radium-223

Therapy

Metastatic CRPC

Radiographic

Metastases:

Castrate

Pre-chemo

Sipuleucel-T

Abiraterone

Enzalutamide

Radium-223

Consensus, Controversy, and Change

in Hormone-Naive Metastatic PC

Consensus: High-volume metastatic disease is

suitable for ADT + 6 cycles of docetaxel

Controversy: Low-volume metastatic disease is

debatable given negative CHAARTED data and no

STAMPEDE data in this subset

Change: STAMPEDE and LATITUDE data are

game changersADT + abiraterone

Chemohormonal Therapy in Metastatic

Hormone-Sensitive Prostate Cancer

Sweeney et al, 2015.

Controversy as P = 0.11

High volume: visceral metastases and/or ≥4 bone metastases

(at least 1 beyond pelvis and vertebral column)

LATITUDE: Abiraterone + Prednisone in

Metastatic Castration-Sensitive PC

OS = overall survival; PFS = progression-free survival; NR = not reached.

Fizazi et al, 2017.

6/4/17 NEJM

Median OS: NR vs 34.7 months Median PFS: 33.0 vs 14.8 months

Inclusion criteria: At least 2/3: Gleason ≥8, ≥3 bone mets, visceral disease

LATITUDE: PSA Progression

Fizazi et al, 2017.

LATITUDE: Adverse Events

ALT = alanine aminotransferase; AST = aspartate aminotransferase.

Fizazi et al, 2017.

Abiraterone Placebo

STAMPEDE: Abiraterone for PC Not

Previously Treated With Hormone Therapy

James et al, 2017.

June 3, 2017

STAMPEDE: OS and FFS

FFS = failure-free survival; PSADT = prostate-specific antigen doubling time.

James et al, 2017.

June 3, 2017

Non-metastatic disease subset included:

At least 2/3: Gleason 8-10, T3/4, PSA>40 and intention to treat with radiation

OR

Previously treated with surgery and at least 1 of the following:

PSA ≥4 and PSADT <6 months, PSA ≥20, N+

Some Implications of LATITUDE

and the “New” STAMPEDE

Biology changes associated with relapse after upfront

abiraterone/prednisone and ADT

The effectiveness of subsequent therapies is likely

altered in (as yet) undefined waysCross-resistance between abiraterone and enzalutamide is well

documented in CRPC

The meaning of CRPC is now changing….Post-ADT or post-ADT + docetaxel or

post-ADT + abiraterone/prednisone?

Should we be using ADT + docetaxel or

ADT + abiraterone/prednisone or a triplet?

What Happens If You Have Very Few

Metastases? Oligometastatic?

Photo courtesy of Eugene Kwon.

Bone metastatic disease can lead to further metastatic

spread!

The Evolutionary History of Lethal

Metastatic Prostate Cancer

Gundem et al, 2015.

Approach to Oligomets: Treatment

of the Primary ± Surgery or Radiation?

Observation

SBRT to mets (delay systemic therapy)

ADT “old” or “new”……how long?New ADT to include abiraterone/prednisone?

ADT + SBRT to mets

ADT + docetaxel

ADT + docetaxel + SBRT to mets

Something for everyone…a true “dealer’s choice”

No one knows the right answer and

current trials are limited!

SBRT = stereotactic body radiation therapy.

Prostate Cancer Clinical States

NCCN, 2017.

Recurrent After Initial Hormonal TherapyHormone Sensitive

Diagnoses: 161,360 Deaths: 26,730

Rising PSA

Salvage Rx,

ADT,

or no therapy

Radiographic

Metastases:

Castrate

1st-Line

Chemo

Docetaxel

Localized

Disease

Local therapy

or no therapy

Rising PSA:

Castrate

No standard

of care

Overt

Metastases

ADT +

docetaxel or

abiraterone

Radiographic

Metastases:

Castrate

Post-chemo

Cabazitaxel

Abiraterone

Enzalutamide

Radium-223

Next

Metastatic CRPC

Radiographic

Metastases:

Castrate

No-chemo

Sipuleucel-T

Abiraterone

Enzalutamide

Radium-223

Prostate Cancer Clinical Trials

aFinal analysis.

BSC = best supportive care.

Berthold et al, 2008; Kantoff et al, 2010; Rathkopf et al, 2014. Beer et al, 2017; Scher et al, 2012; de Bono et al, 2010; Fizazi et

al, 2012; Parker et al, 2013.

Trial Frontline HR Survival (mo)

TAX 327Docetaxel/prednisone vs

mitoxantrone/prednisone0.79 19.2 vs 16.2a

IMPACT Sipuleucel-T vs control 0.78 25.8 vs 21.7a

COU-AA-302Abiraterone/prednisone vs

placebo/prednisone0.81 35.3 vs 31.1a

PREVAIL Enzalutamide vs placebo 0.77 35.3 vs 31.3a

Trial Post-Docetaxel HR Survival (mo)

TROPICCabazitaxel/prednisone vs

mitoxantrone/prednisone0.70 15.1 vs 12.7a

COU-AA-301Abiraterone/prednisone vs

placebo/prednisone0.74 15.8 vs 11.2a

AFFIRM Enzalutamide vs placebo 0.63 18.4 vs 13.6a

TrialFrontline and

Post-DocetaxelHR Survival (mo)

ALSYMPCARadium-223/BSC vs

placebo/BSC0.70 14.9 vs 11.3a

Sequencing, Combinations, and Utility

of Molecular Biomarkers

The Great Unknowns

Many Sequences Can Be Considered,

Not Just Abi/Enza and Vice-Versa

aLarge randomized trials show activity of abi/pred, enza, cabazitaxel, and radium post-docetaxel.

Abi 1st Enza 1st Docetaxel 1st Radium 1st

Abi 2nd ----------- +++ resistance Activea No data

Enza 2nd ++ resistance ------------ Activea No data

Docetaxel 2nd Some data Some data ------------ Some data

Cabazitaxel 2nd Some data Some data Activea No data

Radium 2nd Small data Small data Activea --------------

No randomized trials are available for the post-abi or post-enza space.

No randomized trial for any space except post-docetaxel.

Treatment Sequencing

Many articles can be cited, but huge cross-

resistance between abiraterone and enzalutamide

when used sequentially

Whichever you use first will likely last

Whichever you use second not likely to last

Back-to-back oral hormonal agents may not be the

best option

40% with

≥50 decline

Prospective 2nd-Line Therapy:

Abi > Docetaxel From COU-AA-302

de Bono et al, 2017.

Maximum PSA Decline

3rd-Line Enzalutamide Therapy:

Doc > Abi > Enza

Schrader et al, 2014.

Overall 10/35

(28.6%) with

PSA >50%

decline

17/35 (48.6%)

no response

3rd-Line Cabazitaxel Therapy:

Doc > Abi > Cabazitaxel

Pezaro et al, 2014.

15/37 (40.5%)

PSA ≥50% decline

10/37 (27%)

no response

3rd-Line Cabazitaxel Therapy:

Doc > Abi > Cabazitaxel

Al Nakouzi et al, 2015.

≥50% PSA decline: 28 pts

(35.0%); median OS: 14.3

mo

≥50% PSA decline in

TROPIC study: 39.2%

No correlation between

response to cabazitaxel and

duration on docetaxel or

abiraterone

Cabazitaxel remains active in patients progressing after docetaxel and

abiraterone.

N=79

Biomarkers:

Molecular Stratification

PSA Responses in Enza-Treated

Patients by AR-V7 RNA Status in CTCs

CTCs = circulating tumor cells.

Antonarakis et al, 2014.

PSA Responses in Abi-Treated

Patients by AR-V7 RNA Status in CTCs

Antonarakis et al, 2014.

Nuclear AR-V7 (Antibody) and

Abi/Enza Responsiveness

Scher et al, 2016.

Presence of AR-V7–Positive CTCs and Response to AR-Signaling Inhibitors

Nuclear AR-V7 and

Taxane Responsiveness

Scher et al, 2016.

Circulating-Free DNA Alterations

and Progression

Azad et al, 2015.

AR Copy Number Gain or Selected

Mutations in Cell-Free Plasma DNA in

Abiraterone-Treated Patients

Romanel et al, 2015.

OS: AR Copy Number Gain or Selected

Mutations in Cell-Fee Plasma DNA Prospectively

Tested With Abiraterone

Romanel et al, 2015.

AR 702/878

Which Agent for Which Patient?

Choosing Which Agent May Be Effective,

Not Just Predicting Resistance

DNA-Repair Defects Can Be Inherited,

Somatic, or Both

Robinson et al, 2015.

DNA-Repair Defects and Olaparib

in Metastatic Prostate Cancer

Mateo et al, 2015.

DNA-Repair Defects and Olaparib

in Metastatic Prostate Cancer (cont.)

Mateo et al, 2015.

Biallelic Inactivation of BRCA2 in

Platinum-Sensitive Metastatic CRPC

Cheng et al, 2016.

Cabazitaxel/Carboplatin/G-CSF in

“Aggressive Variant” Prostate Cancer

G-CSF = granulocyte colony-stimulating factor.

Corn et al, 2016.

Incidence of MMR Mutations in

Autopsy CRPC Specimens: 12%

MMR = mismatch repair.

Pritchard et al, 2014.

Pembrolizumab + Enza in CRPC:

Mismatch Repair or More?

MSI = microsatellite instability.

Graff et al, 2016.

MSI

Noted

FDA Announcement May 2017

Pembrolizumab awarded accelerated approval for

cancers with high MSI or DNA mismatch repair-

deficient

No companion diagnostic specified

Estimates 10% of all cancers worldwide?

PTEN Loss as Predictive Biomarker for

Akt Inhibitor Ipatasertib + Abi

rPFS = radiographic progression-free survival; HR = hazard ratio; CI = confidence interval.

de Bono et al, 2016.

PTEN

Loss

PTEN

Loss

PTEN

Loss

No PTEN

Loss

No PTEN

Loss

No PTEN

Loss

N=253

Ipat-

400 + Abi

(n=25)

Ipat-

200 + Abi

(n=25)

Pbo + Abi

(n=21)

Ipat-

400 + Abi

(n=32)

Ipat-

200 + Abi

(n=27)

Pbo + Abi

(n=35)

rPFS events,

n (%)15 (60) 16 (64) 18 (86) 20 (63) 20 (74) 26 (74)

Median PFS

(mo)11.5 11.1 4.6 7.5 4.6 5.6

Unstratified HR 0.39 0.46 0.84 1.13

90% CI 0.22-0.70 0.25-0.83 0.51-1.37 0.69-1.85

P Value 0.0064 0.0285 0.5647 0.6762

PSMA Upregulation With Abi/Enza

PSMA = prostate-specific membrane antigen.

Murga et al, 2015.

PSMA Binding Molecules Can Be Linked to

Therapeutic Isotopes Via a Chelator

Isotopes:

Lu-177

Bi-213

Ac-225

Chatalic et al, 2016.

PSMA Lu-177 Clinical Trials:

Waterfall Plots for PSA

Rahbar et al, 2016.

Multimodality Skills to Optimally

Manage PC in the Near Future

Hormonal therapy

Targeted therapy

Immunotherapy

Chemotherapy

Surgery

Radiation oncology

Nuclear medicine

Molecular pathology

Genetics

Genetic counseling

Case 1

84-year-old frail patient with a history of diabetes,

hypertension, hyperlipidemia, and obesity presents to

the clinic with increasing rib pain

S/p ADT and local radiotherapy for initial diagnosis of

prostate cancer 2 years ago (T3b N1 M0)

Initial PSA was 52 ng/mL and decreased to 2.2 ng/mL,

then despite ongoing ADT, PSA increased to 15 ng/mL

and mild diffuse bone pain

Bone scan reveals metastasis in multiple ribs and

several pelvic lesions. CT reveals 1.5 cm nodes in the

pelvis

Case 1 (cont.)

How would you treat this patient?a. Abiraterone/prednisone

b. Enzalutamide

c. Radium-223

d. Zoledronate/denosumab

e. Combination

Case 2

59-year-old patient with a history of surgery,

Gleason 7, PSA failure, intermittent ADT then bone

metastatic CRPC

Treated initially with abiraterone/prednisone

PSA rise and no symptoms

Case 2 (cont.)

How would you treat this patient?a. Abiraterone/dexamethasone

b. Enzalutamide

c. External beam radiation

d. Zoledronate/denosumab

e. Radium-223

f. Docetaxel

g. Combination

Case 3

61-year-old patient with metastatic CRPC treated

with ADT alone in 2012, then with rising PSA and

multiple bone lesions on bone scan (total >20)

Treated initially with docetaxel with good response

Now progression in bone again with severe focal

hip pain

Germline testing revealed a BRCA2 mutation

No soft tissue lesion

Case 3 (cont.)

How would you treat this patient?a. External beam radiation

b. Abiraterone

c. Enzalutamide

d. Radium-223

e. Cabazitaxel

f. Zoledronic acid/denosumab

g. Carboplatin

h. Combination

Key Takeaways

CRPC is evolving into a molecularly targeted

disease for a growing subset of patients

AR remains our most proven target and much can

be gained by CRPC treatment with the new AR-

targeted agents, but cross-resistance is a major

issue

Much progress has been made, but we have a long

way to go, especially for those progressing after

AR-targeted therapy and taxanes

Questions?

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