Treatment Sequences: How to Decide?€¦ · CRPC, so this will not be discussed. • The rubric of...

Treatment Sequences: How to Decide?

David F. Penson, MD, MPH

Professor of Urologic Surgery

Director, Center for Surgical Quality and Outcomes Research

Vanderbilt University Medical Center

Nashville, TN

Financial and Other Disclosures • Off-label use of drugs, devices, or other agents: none

• Data from IRB-approved human research is presented

I have the following financial interests or

relationships to disclose: Disclosure code

Astellas Consultant

Dendreon Consultant

Medivation Consultant

Astellas, Dendreon, Medivation, Chronix Research Support

AHRQ, NCI, PCORI, CDC Research Support

A Few Important Caveats

• There are no FDA approved agents in M0

CRPC, so this will not be discussed.

• The rubric of parsing M1 CRPC patients

into asymptomatic/minimally symptomatic

and symptomatic categories (as proposed in

AUA guidelines) is useful.

• There are no definitive, prospective RCTs

comparing the various agents, so much of

this presentation represents opinion.

Cookson, et al: J Urol, 2013

Lorente, et al: Lancet Oncol, 2015

ASYMPTOMATIC/MINIMALLY

SYMPTOMATIC M1 CRPC

AUA Guidelines: Index Patient 2: Asymptomatic/minimally symptomatic and good

functional status

• Standard recommendation (evidence grade): – abiraterone/prednisone (A)

– docetaxel (B)

– enzalutamide (A)

– sipuleucel-T (B)

• Option recommendation (evidence grade): – 1st generation anti-androgen (i.e bicalutamide) (C)

– Ketoconazole/steroid (C)

– Observation (C)


http://www.auanet.org/education/guidelines/castration-resistant-prostate-cancer.cfm

Is there a role for 1st generation anti-androgens

in M1 CRPC?: Enzalutamide vs. Bicalutamide

The STRIVE trial

• M0 or M1 CRPC

• Asym/Minimally Sym.

• PSADT <10 mos

• 396 men total (1:1 RCT)

– M0= 139

– M1= 257

• Accrued from 8/12-3/14

• Primary outcome:

progression-free survival

(defined as PSA

progression, clinical event

or death

The TERRAIN trial

• M1 CRPC

• Asym/Minimally Sym.

• PSA <50 ng/ml

• 375 men total (1:1 RCT)

• Median f/u time

– 20 mos in Enza group

– 16.7 in bicalutamide group

• Primary outcome:

progression-free survival

(defined as clinical event

or death)

Penson et al: JCO, 2016

Shore, et al: Lancet Oncol, 2016

Is there a role for 1st generation

anti-androgens in M1 CRPC?

M1 only

Median

PFS:15.7 vs. 5.8

mos

Penson et al: JCO, 2016

Shore, et al: Lancet Oncol, 2016

Pivotal trials of CRPC agents in asymptomatic

or minimally symptomatic patients

Trial Author n Experimental

group

Control group(s) Median

Overall

Survival

Comments

TAX-327 Tannock, et al,

NEJM, 2004

1006 Docetaxel

75mg/m q3w

-Mito. 12mg/m q3w

-Docetaxol 30 mg/m

q3w

D75: 18.9 mos

M: 16.5 mos

D30: 17.4 mos

-45% of pts with

pain at baseline

COU-AA-

302

Ryan, et al,

NEJM, 2013

1088 Abiraterone

1000mg qd plus

Prednisone 5mg

bid

Placebo plus prednisone

5 bid

NR vs. 27.2 mos

(Radiographic

PFS- 16.5 vs 8.3

mos)

-OS did not meet

pre-specified

significance

criteria

-no prior chemo.

IMPACT Kantoff, et al,

NEJM, 2010

512 Sipuleucel-T

every 2 weeks

for 3 infusions

Placebo 25.8 vs 21.7 mos -No differences in

PFS

-no visceral mets

-19.6% post-

chemo

PREVAIL Beer, et al,

NEJM, 2014

1715 Enzalutamide

160 mg qd

Placebo 32.4 vs. 30.2 mos -11% of patients

had visceral

disease

Adapted from Lorente, et al, Lancet Oncol, 2015

What is the role of Sipuleucel-T in the

era of oral agents? PROS

• Is relatively non-toxic

• IMPACT study showed an OS advantage

• Different mechanism of action

CONS

• Can be logistically challenging to give

• Expensive

• Is only available in the United States

• Some controversy around IMPACT

IMPACT Overall Survival: Primary Endpoint

Intent-to-Treat Population

0 6 12 18 24 30 36 42 48 54 60 660

25

50

75

100

Perc

ent

Surv

ival

Survival (Months)

P = 0.032 (Cox model)

HR = 0.775 [95% CI: 0.614, 0.979]

Median Survival Benefit = 4.1 Mos.

No difference in PFS

Sipuleucel-T (n = 341)

Median Survival: 25.8 Mos.

Placebo (n = 171)

Median Survival: 21.7 Mos.

Kantoff, et al, NEJM, 2010

Sequencing Sipuleucel-T in CRPC

• Likely most effective in men with minimal disease

early in CRPC course – Asymptomatic

– Lower PSAs

– Slower doubling times

– Low-volume disease

– Greater than 6 month life expectancy

• Not appropriate for men with: – Limited life expectancy

– Symptomatic disease

– Rapidly progressing disease (fast PSADT)

– High volume disease

– Visceral metastases (?)

Docetaxol in asymptomatic or

minimally symptomatic patients

• Recommended by both AUA and NCCN as possible 1st

line therapy in these patients

• Patients are often reluctant to proceed with docetaxol

given side-effect profile (fatigue, neuropathy, bone

marrow suppresion)

– 26% of patients in Tax-327 had one or more SAE

– 11% discontinued therapy

• Patients who might be considered for upfront docetaxol

– Younger patients with good performance status

– Rapidly progressing or high volume disease

https://www.nccn.org/professionals/physician_gls/pdf/prostate_blocks.pdf


Tannock, et al, NEJM, 2004

Enzalutamide vs Abiraterone: Asymptomatic/minimally symptomatic, pre-chemo pt

Enzalutamide

• Androgen receptor signaling

inhibitor

• Contraindicated in men with

seizure history

• Side effects include:

– Fatigue (sometimes profound)

– Hypertension

– GI side effects

(constipation/diarrhea)

– Seizure risk

• Preferred in pts who cannot

tolerate systemic steroids (brittle

DM, gastric ulcer disease)

Abiraterone

• Androgen synthesis inhibitor

(binds the cytochrome P450

(CYP17) gene)

• Normally given with

corticosteroids (pred 5 bid)

• Side effects include:

– Hypertension

– Hypokalemia

– Fatigue

– Steroid-induced hyperglycemia

• Preferred in pts with seizure

history

Enzalutamide vs. Abiraterone: The problem of cross-resistance

Zhang, et al, Expert Opin. Pharmacother., 2015

SYMPTOMATIC M1 CRPC

PATIENTS

AUA Guidelines: Index Patient 3: Symptomatic and good functional status who has not had

prior docetaxol


– docetaxel (B)


– radium-223 (in pts w/o visceral mets) (B)

• Option recommendation (evidence grade): – Ketoconazole/steroid (C), Mitoxantrone (B) or

radionuclide therapy (C) IN PATIENTS WHO DO

NOT WANT DOCETAXOL



• Radiopharmaceutical

– Bone-seeking isotope that mimics calcium

– Forms complexes with hydroxyapatite and is incorporated into areas of bone turnover

• Osteoblastic lesions

– α particles cause double-stranded breaks in DNA

• High-energy particles, travel 40-100 µm

• Minimal damage to surrounding tissue

Radium-223

Parker C, et al. NEJM. 2013

Nilsson S, et al. European J Cancer. 2012

Sartor O, et al. Lancet Oncol. 2014

Parker C, et al. NEJM. 2013

• Which patients?

– FDA approved for men with mCRPC with

symptomatic bone metastases before or after

chemotherapy.

• Side Effects

– Bone marrow suppression, refractory cytopenias

(rare)

• Which patients are poor candidates?

– History of bone marrow dysfunction

– Visceral disease

Radium-223

TREATING CRPC IN THE

POST-DOCETAXEL SETTING

AUA Guidelines: Index Patient 5: Symptomatic and good functional status who has had

prior docetaxol therapy


– cabazitaxel (B)


– radium-223 (in pts w/o visceral mets) (B)

• Option recommendation (evidence grade): – Ketoconazole/steroid (C) if other options unavailable

– Docetaxel retreatment (C) in patients who were

benefitting from docetaxel at time of discontinuation

due to side effects Cookson, et al: J Urol, 2013


Pivotal trials of CRPC agents in post-docetaxel

patients

Trial Author n Experimental

group

Control group(s) Median

Overall

Survival

Comments

TROPIC de Bono,

et al,

Lancet,

2010

755 cabazitaxel

25mg/m q3w

-Mito. 12mg/m q3w

15.1 vs. 12.7 mos -Significant

hematologic AEs in

Cabazitaxel group

-No difference in

pain

COU-AA-301 Fizazi, et

al, Lancet

Oncol

2012

1195 Abiraterone

1000mg qd plus

Prednisone 5mg bid

Placebo plus

prednisone 5 bid

14.8 vs 10.9 mos -none

ALSYMPCA Parker, et

al, NEJM,

2013

809 Radium-223 50kBq

every 4 wks for 6

cycles

Placebo 14 vs 11.2 mos --57% of pts were

post-docetaxel

-visceral mets

excluded

AFFIRM Scher, et

al, NEJM,

2012

1199 Enzalutamide 160

mg qd

Placebo 18.4 vs. 13.6 mos -none

Adapted from Lorente, et al, Lancet Oncol, 2015

WHERE DO WE GO FROM

HERE?

Biomarkers to personalize treatment sequencing

Antonarakis ES, et al. NEJM. 2014

AR-V7 and resistance to enzalutamide

and abiraterone in CRPC

Selecting Therapy Based on AR-V7 Status

Scher, et al. JAMA Oncol. 2016

Future Directions in CRPC Therapy Sequencing

• Sequencing based on molecular markers

– TMPRSS2-ERG, PTEN, BRCA

• Novel therapies based on markers

– Carboplatin + cabazitaxel in aggressive

variant CRPC

• Modifications to current therapeutic

regimens

– Intermittent docetaxel therapy

– Combination therapies

Cash, et al. ASCO Annual Mtg, Chicago, 2016

Aparicio, et al. ASCO Annual Mtg, Chicago, 2016

Asymptomatic or

Minimally

symptomatic CRPC

patient

Low-

volume

and/or

slowly

rising

PSA?

Sipuleucel-T

Abiraterone/prednisone

Enzalutamide

progression

Fit for treatment with

docetaxel? Docetaxel

Radium-223

-bone mets only

-good hematologic

function

YES

NO

Choice based

on Pt

characteristics

and

preferences

Consider trial with

alternative oral agent

or observation until

symptomatic

ASYMPTOMATIC

SYMPTOMATIC

YES

NO Abi or Enza (if not

previously tried)

PROGRESSION NO

Cabazitaxel

(in appropriate

selected and

motivated patients)

Our General Algorithm

Treatment Sequences: How to Decide?€¦ · CRPC, so this will not be discussed. • The rubric of...

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