Treatment Sequences: How to Decide?€¦ · CRPC, so this will not be discussed. • The rubric of...
Transcript of 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)
Cookson, et al: J Urol, 2013
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
Cookson, et al: J Urol, 2013
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
• Standard recommendation (evidence grade): – abiraterone/prednisone (A)
– docetaxel (B)
– enzalutamide (A)
– 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
Cookson, et al: J Urol, 2013
http://www.auanet.org/education/guidelines/castration-resistant-prostate-cancer.cfm
• 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
• Standard recommendation (evidence grade): – abiraterone/prednisone (A)
– cabazitaxel (B)
– enzalutamide (A)
– 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
http://www.auanet.org/education/guidelines/castration-resistant-prostate-cancer.cfm
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