1. Bones, Hot Flashes, and ADT Use With Chemotherapy and Timing
Thomas E. Keane
Medical University of South Carolina
Charleston, SC

2. Toxicities of ADT
Hot 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;67:825-36

3. Strategies to Mitigate Side effects of ADT
Intermittent ADT – Rising PSA after local RX
Reducing the duration of ADT – No data in metastatic DZ : 6 worse than 36 in RT failure
Antiandrogen monotherapy – Inferior to ADT
Exercise therapy
Crook JM, et al. N Eng J Med 2012;367:
Smith MR, et al. J Clin Oncol 2004;22:
Bolla M, et al. N Engl J Med 2009;360:
Cormie P, et al. Prostate Cancer Prostatic Dis 2013;16;170-5

4. Intermittent vs. Continuous ADT 7 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 lack 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; 34:280-5

5. 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;67:825-36

6. 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:

7. Management of Hot Flashes
Adverse events with all – GI, Vascular and CNS

8. 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
Men with prostate cancer on ADT treated with acupuncture
-reduction in severity of hot flash score from %
-greater than 50% reduction in daily number of hot flashes
Hirsch L, Goldstein L. Canadian Journal of Urology 2015; 22:7938

9. Management of Hot Flashes
Acupuncture:
Proposed mechanism of action:
Acupuncture stimulates release of serotonin and norepinephrine in hypothalamic regulatory center
Modulates peripheral autonomic nervous system

10. 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;28:634-40

11. ADT and Bone Health ADT accelerates bone loss in men
Bone 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:
Shahinian VB, et al. N Engl J Med. 2005;352:154-64

12. 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 ADT

13. ADT and Bone Health-Prevention
1200 mg calcium and 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 IU/day vitamin D (National Osteoporosis Foundation)
Bisphosphonates
Denosumab
SERMs

14. 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: – weekly Alendronate increased Spine BMD 1.7% vs -1.9% with Ca and Vit D alone.

15. ADT and Bone Health- Prevention
Bisphosphonates (zoledronic acid, alendronate):
Meta-analysis of 15 trials and 2634 subjects: bisphosphonates as a class
prevented fractures and osteoporosis (RR 0.8 and 0.39 respectively)
Serpa Neto A, et al. Prostate Cancer Prostatic Dis 2012;15:36-44

16. Denosumab: Humanized Monoclonal Antibody Against NF-KB
Blocks maturation of preosteoclasts to osteoclasts
Prevents bone resorption
Healthplexus.net /article/bone-biology-and-role-rankranklopg-pathway

17. ADT and Bone Health-Prevention
Denosumab:
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)
Smith MR, et al. N Engl J Med 2009;361:745-55

18. ADT and Bone Health-Prevention
Selective estrogen receptor modulators (raloxifene, toremifine)
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 events
Smith MR, et al. J Urol 2010;184:

19. ADT and Bone Health-Prevention
NCCN guidelines
For men with a 10 year risk of hip fracture >3% based on the FRAX algorithm
1200 mg calcium, IU vitamin D
AND either
-denosumab 60mg SQ every 6 months OR
-zolendronic acid 5mg IV annually
-alendronate 70 mg PO weekly

20. Personalized ADT for the Specific Patient
Cardiac
Obesity and testosterone
Fsh
High volume metastatic disease
Docetaxol
Significant LUTS

21. Sources of Androgen Production
Androgens are produced at 3 sites:
Testes
Adrenal gland
Prostate tumor cells (NEW DISCOVERY!)

22. Reversible AR blockers[1,2]
Before 2010, the last agent approved for the treatment of CRPC was docetaxel
Denosumab[9]
Sipuleucel-T[8]
Zoledronic Acid[4]
Abiraterone Post[10]
LHRH agonists[1,2]
Cabazitaxel [7]
Mitoxantrone[3]
Enzalutamide Post[11]
Docetaxel[5,6]
1996
2002
2004
2010
2011
2013
2014
....
2012
Reversible AR blockers[1,2]
Abiraterone Pre[13]
Radium-223[12]
Enzalutamide Pre [14]
The Leuprolide Study Group. NEJM 1984;311: Crawford ED, et al. NEJM. 1989;321: Tannock IF, et al. J Clin Oncol. 1996;14: Saad F, et al. JNCI 2002;94: Petrylak DP, et al. NEJM. 2004;351: Tannock IF, et al. NEJM. 2004;351: de Bono JS, et al. Lancet. 2010;376: Kantoff PW, et al. NEJM. 2010;363: Fizazi K, et al. Lancet. 2011;377: de Bono JS, et al. NEJM. 2011;364: Scher HI, et al. NEJM Sep 27;367(13): Parker et al. NEJM. 2013;369: Beer T et al ASCO GU San Francisco, CA 14. Beer T NEJM 2014; 371:

23. New Concept
Should these advances be applied to Hormone Sensitive Prostate Cancer and if so:
Which agents and when

24. Discussion Topics E3805 (CHAARTED) data review
Comparison with GETUG-AFU 15
Who really should receive docetaxel? The high vs. low volume/risk disease debate
Safety and toxicity considerations

25. E3805 CHAARTED: ChemoHormonal Therapy vs
E3805 CHAARTED: ChemoHormonal Therapy vs. Androgen Ablation for Metastatic Prostate Cancer
ARM A:
ADT + Docetaxel 75mg/m2 every 21 days for maximum 6 cycles
Evaluate every 3 weeks while receiving docetaxel and at week 24 then every 12 weeks
Stratification
Extent of Mets
High vs Low
Age
≥70 vs < 70yo
ECOG PS
- 0-1 vs 2
CAB> 30 days
-Yes vs No
SRE Prevention
Prior Adjuvant ADT
≤12 vs > 12 months
Randomize
Follow for time to progression and overall survival
Chemotherapy at investigator’s discretion at progression
Original design n=568 for high volume disease
Adjustments for allowance of low volume disease and projected OS based on S9346 data n=780
ARM B:
ADT (androgen deprivation therapy alone)
Evaluate every 12 weeks
ADT allowed up to 120 days prior to randomization
Intermittent ADT dosing was not allowed
Standard dexamethasone premedication but NO DAILY PREDNISONE
Sweeney C et al. ASCO 2014; Abstract LBA2.

26. E3805 CHAARTED: ChemoHormonal Therapy vs
E3805 CHAARTED: ChemoHormonal Therapy vs. Androgen Ablation for Metastatic Prostate Cancer
N=790 men accrued 07/28/ /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 survival
Sweeney C et al. ASCO 2014; Abstract LBA2.

27. OS by extent of metastatic disease at start of ADT
E3805 CHAARTED: ChemoHormonal Therapy vs. Androgen Ablation for Metastatic Prostate Cancer
OS by extent of metastatic disease at start of ADT
>4 bone lesions and
>1 lesion in any bony structure
beyond the spine/pelvis OR
visceral disease
p=0.0006
HR=0.60 ( )
Median OS:
ADT + D: 49.2 months
ADT alone: 32.2 months
p=0.1398
HR=0.63 ( )
Median OS:
ADT + D: Not reached
ADT alone: Not reached
High volume
Low volume
Sweeney C et al. ASCO 2014; Abstract LBA2.

28. Biochemical PFS Overall Survival HR=0.72 (0.57-0.91) p=0.005
Median OS:
ADT + D: 22.9 months
ADT alone: 12.9 months
HR=1.01 ( ) p=0.955
Median OS:
ADT + D: 58.9 months
ADT alone: 54.2 months
Biochemical PFS
Overall Survival
Gravis et al. Lancet Oncol ; 14:

29. Key Differences between GETUG-AFU 15 and CHAARTED
385
790
Docetaxel cycles
Up to 9 (median 8) 6
Gleason 8-10
56.1%
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)

30. Study size/statistical power
Summary of Factors that may have Contributed to Different Results between GETUG-AFU 15 and CHAARTED
Study size/statistical power
Prognosis and staging definitions and disease risk/volume were different
? Toxicity e.g. deaths and early discontinuations and the use of other subsequent therapies were different

31. Grade 3-5 Hematologic Toxicity from TAX327 in mCRPC vs. GETUG-AFU 15 vs. 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
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?
Tannock IF et al. N Engl J Med 2004; 351:

32. 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
50% decrease in docetaxel clearance associated with >430% increase in odds of grade ¾ neutropenia*
Franke RM et al. J Clin Oncol 2010; 28: ; *Bruno R et al. J Clin Oncol 1998; 16:

33. What are the Implications of these PK Differences?
Between Different Trials
For the Practicing Clinician
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?
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 castrate

34. Question
If toxicity is greater with the use of Docetaxol in the pre- castrate state might not efficacy also be?
We need a trial.

35. 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.