Medical University of South Carolina Charleston SC Bones Hot Flashes and ADT Use With Chemotherapy and Timing Toxicities of ADT Hot Flashes sexual dysfunction and many other complications of therapy are seen in greater than 90 of men on ADT ID: 591212
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Slide1
Thomas E. Keane
Medical University of South Carolina Charleston, SC
Bones, Hot Flashes, and ADT Use With Chemotherapy and TimingSlide2
Toxicities of ADTHot Flashes, sexual dysfunction and many other complications of therapy are seen in greater than 90% of men on ADT
Higano
CS. J
Clin
Oncol
. 2012;30:3720-5
Nguyen PL, et al.
Eur
Urol. 2015;67:825-36Slide3
Strategies to Mitigate Side effects of ADT
Intermittent ADT – Rising PSA after local RXReducing the duration of ADT – No data in metastatic DZ : 6 worse than 36 in RT failureAntiandrogen monotherapy – Inferior to ADT
Exercise therapy
Crook JM, et al. N
Eng
J Med 2012;367:895-903
Smith MR, et al. J
Clin
Oncol 2004;22:2546-53Bolla M, et al. N Engl J Med 2009;360:2516-27Cormie P, et al. Prostate Cancer Prostatic Dis 2013;16;170-5Slide4
Intermittent vs. Continuous ADT7 published phase 111 trials revealed concerns related to design and interpretation
Survival is worse in IAD for patients with
metastatic disease
compared to CAD
Median OS differences of 8-10 months in CAD vs. IAD
A l
ack of statistically significant inferiority of IAD does not equal clinically insignificant differences
Combined data from RCTs does not support large or durable effects on QOL: due to short follow-up time
ans
small underpowered trials Hussain M, et al. J Clin Oncol. 2016; 34:280-5Slide5
Hot Flashes and ADT
Over 50% of men on ADT experience hot flashes
ADT lowers set point resulting in easier activation….
Allan CA, et al.
Endocr
Relat
Cancer. 2014;21:119-29
Nguyen PL, et al.
Eur
Urol. 2015;67:825-36Slide6
Management of Hot Flashes
Medroxyprogesterone acetate
Irani
J, et al. Lancet
Oncol
2010;11:147-54
Harding C, et al. BJU
Int
2009;103:186-90
Ashamalla H, et al. Int J Radiat Oncol
Biol
Phys 2011;79:1358-63Slide7
Management of Hot Flashes
Adverse events with all – GI, Vascular and CNS Slide8
Management of Hot Flashes
Acupuncture: Prospective studies: 85-90% improvement
Twice weekly sessions for 6 weeks
12 acupuncture sites
Needles left in place for 45 minutes
Hirsch L, Goldstein L. Canadian Journal of Urology 2015; 22:7938
Men with prostate cancer on ADT treated with acupuncture
-reduction in severity of hot flash score from 70-89.2%
-greater than 50% reduction in daily number of hot flashes Slide9
Management of Hot FlashesAcupuncture:
Proposed mechanism of action:Acupuncture stimulates release of serotonin and norepinephrine in hypothalamic regulatory centerModulates peripheral autonomic nervous systemSlide10
Management of Hot Flashes
Acupuncture:
RCT comparing 12 weeks of acupuncture versus venlafaxine in breast cancer patients on hormone therapy with
tamoxifen
Walker et al. J
Clin
Oncol
. 2010;28:634-40Slide11
ADT and Bone Health
ADT accelerates bone loss in menBone mineral density decreases 5-10% at 1 yr and begins within 6-9 months of ADT initiation
Increase bone turnover = increase fracture risk
Up to a 21% relative increase in clinical fractures on ADT
Smith MR, et al. J
Clin
Oncol
2005;23:7897-903Shahinian VB, et al. N Engl J Med. 2005;352:154-64Slide12
Fracture Risk Assessment Tool (FRAX)
For men with a 10 year risk of hip fracture >3% based on this tool, a baseline bone mineral density scan should be obtained before initiating ADT, followed by a scan after 1 year of therapy for men on long-term ADTSlide13
ADT and Bone Health-Prevention
1200 mg calcium and 800-1000 IU vitamin D
No RCT have been performed to evaluate whether supplementation improves bone mineral density for patients on ADT
However, it is reasonable to recommend 1200 mg calcium and 800-1000IU/day vitamin D (National Osteoporosis Foundation)
Bisphosphonates
Denosumab
SERMsSlide14
ADT and Bone Health- Prevention
Bisphosphonates (zoledronic acid, alendronate): RCTs show increased BMD or reduced BMD loss
Klotz LH et al.
Eur
Urol
2013;63:927-35 – weekly Alendronate increased Spine BMD 1.7%
vs
-1.9% with Ca and
Vit D alone.Slide15
ADT and Bone Health- Prevention
Bisphosphonates (
zoledronic
acid, alendronate):
Serpa
Neto
A, et al. Prostate Cancer
P
rostatic Dis 2012;15:36-44
M
eta-analysis of 15 trials and 2634 subjects: bisphosphonates as a class
prevented fractures and osteoporosis (RR 0.8 and 0.39 respectively) Slide16
Denosumab: Humanized
M
onoclonal
A
ntibody Against NF-KB
Blocks maturation of
preosteoclasts
to osteoclasts
Prevents bone resorptionHealthplexus.net /article/bone-biology-and-role-rankranklopg
-pathwaySlide17
ADT and Bone Health-Prevention
Denosumab:
Smith MR, et al. N
Engl
J Med 2009;361:745-55
RCT of 1468 men:
-increased lumbar spine BMD at 24 months by 5.6%
vs
1% loss in the placebo
-decreased incidence in new vertebral fractures at 3 years (1.5%
vs
3.9%, RR 0.38) Slide18
ADT and Bone Health-Prevention
Selective estrogen receptor modulators (raloxifene, toremifine
)
Smith MR, et al. J
Urol
2010;184:1316-21
SERMS improve mean BMD and reduce incidence of new fractures by 50% compared to placebo in men on ADT
However not FDA approved due to increased incidence in venous
thromboembolic
eventsSlide19
ADT and Bone H
ealth-PreventionNCCN guidelinesFor men with a 10 year risk of hip fracture >3% based on the FRAX algorithm
1200 mg calcium, 800-1000 IU vitamin D
AND either
-denosumab
60mg SQ every 6 months
OR
-zolendronic acid 5mg IV annually OR -alendronate 70 mg PO weeklySlide20
Personalized ADT for the Specific Patient
CardiacObesity and testosteroneFshHigh volume metastatic diseaseDocetaxol
Significant LUTSSlide21
Sources of Androgen Production
Androgens are produced at 3 sites:
Testes
Adrenal gland
Prostate tumor
cells (NEW DISCOVERY!)Slide22
1984-1989
The Leuprolide Study Group. NEJM 1984;311:1281-1286. 2. Crawford ED, et al.
NEJM. 1989;321:419-424. 3.
Tannock IF, et al. J Clin Oncol. 1996;14:1756-1764. 4.
Saad F, et al. JNCI 2002;94:1458-1468.
5. Petrylak DP, et al. NEJM. 2004;351:1513-1520.
6. Tannock IF, et al.
NEJM. 2004;351:1502-1512.
7.
de Bono JS, et al. Lancet. 2010;376:1147-1154.
8. Kantoff PW, et al. NEJM. 2010;363:411-422. 9. Fizazi K, et al. Lancet. 2011;377:813-822. 10.
de Bono JS, et al. NEJM. 2011;364:1995-2005.
11.
S
cher
HI, et al.
NEJM.
2012 Sep 27;367(13):
1187-97.
12.
Parker et al.
NEJM
. 2013;369:213-223.13.
Beer
T et al. 2014 ASCO
GU
San Francisco,
CA 14. Beer T
NEJM
2014;
371:424-433
1996
2002
2004
....
2010
2011
2012
Mitoxantrone
[3]
Docetaxel
[5,6]
Sipuleucel-T
[8]
LHRH agonists
[1,2]
Abiraterone Post
[10]
Reversible AR blockers
[1,2]
Denosumab
[9]
2014
Cabazitaxel
[7]
Abiraterone Pre
[13]
Enzalutamide Pre
[14]
Radium-223
[12]
Before 2010, the last agent approved for the treatment of CRPC was docetaxel
Zoledronic Acid
[4]
Enzalutamide Post
[11]
2013Slide23
New Concept Should these advances be applied to Hormone Sensitive Prostate Cancer and if so:
Which agents and when Slide24
Discussion TopicsE3805 (CHAARTED)
data reviewComparison with GETUG-AFU 15Who really should receive docetaxel? The high vs. low volume/risk disease debateSafety and toxicity considerationsSlide25
E3805 CHAARTED: ChemoHormonal Therapy vs. Androgen Ablation for Metastatic Prostate Cancer
Stratification
Extent of Mets
High
vs
Low
Age
≥70
vs
< 70yoECOG PS- 0-1 vs 2CAB> 30 days-Yes vs No
SRE Prevention
-Yes
vs
No
Prior Adjuvant ADT
≤12
vs
> 12 months
Randomize
ARM A:
ADT +
Docetaxel
75mg/m2 every 21 days for maximum 6 cycles
ARM B:
ADT (androgen deprivation therapy alone)
Evaluate every 3 weeks while receiving
docetaxel
and at week 24 then every 12 weeks
Evaluate every 12 weeks
Follow for time to progression and overall survival
Chemotherapy at investigator’s discretion at
progression
Sweeney C et al. ASCO 2014; Abstract LBA2.
ADT allowed up to 120 days prior to randomization
Intermittent ADT dosing was not allowed
Standard dexamethasone premedication but NO DAILY PREDNISONE
Original design n=568 for high volume disease
Adjustments for allowance of low volume disease and projected OS based on S9346 data n=780 Slide26
E3805 CHAARTED: ChemoHormonal Therapy vs. Androgen Ablation for Metastatic Prostate Cancer
Sweeney C et al. ASCO 2014; Abstract LBA2.
N=790 men accrued 07/28/06 - 11/21/12
Planned interim analysis at 53% information met 10/13
01/16/14 median
followup
29 months
136 (110 high volume) deaths ADT alone vs. 101 (82 high volume) deaths ADT+D
83.6% vs. 83.2% of deaths from prostate cancer
Primary endpoint – Overall survivalSlide27
E3805 CHAARTED: ChemoHormonal Therapy vs. Androgen Ablation for Metastatic Prostate Cancer
OS by extent of metastatic disease at start of ADT
Sweeney C et al. ASCO 2014; Abstract LBA2.
p=0.0006
HR=0.60 (0.45-0.81)
Median OS:
ADT + D: 49.2 months
ADT alone: 32.2 months
p=0.1398
HR=0.63 (0.34-1.17)
Median OS:
ADT + D: Not reached
ADT alone: Not reached
>
4 bone lesions
and
>
1 lesion in any bony structure
beyond
the spine/pelvis
OR
visceral disease
High volume
Low volumeSlide28
Gravis et al. Lancet
Oncol
. 2013; 14:149-58.
HR=1.01 (0.75-1.36) p=0.955
Median OS:
ADT + D: 58.9 months
ADT alone: 54.2 months
HR=0.72 (0.57-0.91) p=0.005
Median OS:
ADT + D: 22.9 months
ADT alone: 12.9 months
Overall Survival
Biochemical PFSSlide29
GETUG-15
CHAARTED
N
385
790
Docetaxel
cycles
Up to 9 (median 8)
6
Gleason 8-1056.1%68.6%PSA median (ng/mL)
ADT 25.8; ADT+D 26.7
ADT 50.5; ADT+D 56.0
High volume/risk
21.6%
1
65.1%
2,3
Discontinuations
early for toxicity
20.3%
12.5%
Treatment
related deaths
4 (2.1%)
1 (0.3%) but 8 (2%) unknown
Median
followup
50 months (data cutoff July
31, 2011)
29 months
Subsequent
docetaxel
with CRPC (%)
ADT (62); ADT+D (28)
ADT 129/174 (74.1) ; ADT+D 49/145 (33.8)
Subsequent potent AR therapy with CRPC (%)
ADT (<15); ADT+D (<16)
ADT 79/174 (45.5); ADT+D 92/145 (62.8)
Key Differences between GETUG-AFU 15 and CHAARTED Slide30
Summary of Factors that may have Contributed to Different Results between GETUG-AFU 15 and CHAARTED
Study size/statistical powerPrognosis and staging definitions and disease risk/volume were different? Toxicity e.g. deaths and early discontinuations and the use of other subsequent therapies were differentSlide31
Grade 3-5 Hematologic Toxicity from TAX327 in mCRPC vs. GETUG-AFU 15 vs. CHAARTED
Toxicity
TAX327 (%)
GETUG-AFU
15 (%)
CHAARTED (%)
Neutropenia
32
32*
12
Febrile
neutropenia
3
7*
6
Death
0.3
2.1
0.3^
*After 56% accrual and 4 treatment-related deaths, DSMC recommended GCSF days 5-10 with Grade ¾ neutropenia rate decline from 41% to 15%, febrile neutropenia decline from 8% to 6% and no more deaths.
^2% of deaths were unknown
Tannock
IF et al. N
Engl
J Med 2004; 351:1502-12.
Key Conclusion
:
Tough
to interpret toxicity data with incomplete information on growth factors
and prophylactic
antibiotics, but, is there some a sense that
docetaxel
may surprisingly be more toxic in
mHSPC
? Slide32
Docetaxel PK varies with Castration State
10 non-castrate and 20 castrate men with similar demographics
Clearance of
docetaxel
in castrate men was 100% increased with 2 fold reduction in AUC
Erythromycin breath test indicated hepatic CYP3A4 activity, for
docetaxel
metabolism, was not different
Castrate rats have higher AUC of
docetaxel
in liver compared to intact animals
Franke
RM et al. J
Clin
Oncol
2010; 28:4562-67; *Bruno R et al. J
Clin
Oncol
1998; 16:187-96.
50% decrease in
docetaxel
clearance associated with >430% increase in odds of grade ¾ neutropenia*Slide33
What are the Implications of these PK Differences?
Between Different Trials
May explain some of the greater hematologic toxicity but also survival benefit observed in castration-sensitive compared to castration-resistant trials
Why was there greater hematologic toxicity in GETUG-AFU 15 compared to CHAARTED?
How many patients were non-castrate vs. castrate in each trial?
GETUG-AFU 15: 47% initiated ADT within 15 days of enrollment
CHAARTED: initiated ADT median 1.1 months to enrollment
How much GCSF was used in each trial?
For the Practicing Clinician
Consider waiting until after 1-2 months of ADT or castrate testosterone levels have been reached before starting
docetaxel
?
Use GCSF, at least for the first couple cycles, until castrateSlide34
Question If toxicity is greater with the use of
Docetaxol in the pre- castrate state might not efficacy also be?We need a trial.Slide35
A phase II study of docetaxel before medical castration with degarelix in patients with newly diagnosed metastatic prostatic adenocarcinoma.
N = 50 patients
Enrolling men with newly diagnosed treatment naïve metastatic prostate cancer of all volume statuses.
Primary Endpoint – Proportion of men who maintain a PSA
<
0.2 ng/ml at 40 weeks on study(7 months ADT)
Additional Endpoints – Toxicity, PSA response to Docetaxel alone, time to development of castration resistance, overall survival, correlating genomics with response.