Intermittent Androgen

Deprivation Therapy (ADT):

Benefits outweigh risks

Laurence Klotz

Professor of Surgery

Sunnybrook Health Sciences Centre

University of Toronto

Advantages of intermittent ADT

• Likely:

– Improved QOL with recovery of testosterone (hot flashes, libido, erectile function, frailty, etc.)

– Reduced morbidity and mortality (metabolic syndrome, CV disease,diabetes, bone mineral density loss)

– Reduced drug costs

• Potential:

– Re-exposure of stem/progenitor cells to androgen may prolong duration of androgen dependence (demonstrated in murine models)

– Opportunity for integrated therapy with cell cycle directed interventions

Sex Steroids as Tumor Suppressors in Breast and

Prostate Cancer

Actuarial survival of intermittent bicalutamide

(AA) monotherapy verses LHRH agonist +/- AA

(Int LHRH) Oliver T, FOIUS 2016

P=.005

0.0

00

.25

0.5

00

.75

1.0

0

0 1 2 3 4 5 6 7 8 9 10Years

AA Int LHRH

Trial Stage N Results

SEUG (Portugal) T3,4 or M1 914 No difference in OS

AP17/95 (Germany) T3,4 or M1 335 No difference in TTP or OS

EC507 (Europe) Post RP rising PSA 167 No difference TTP

Erasmus M1 366 QOL better

FinnProstate VII T3,4, M1 564 No difference

TULP (Netherlands) T3,4, M1 193 No difference

De Leval (Belgium) T3,4, M1, post RP 68 TTP favoring Intermittent

Yamanaka T3,4, adjuvant 188 No difference

Hering (Brazil) M1 43 Trend favoring intermittent

Earlier Phase 3 Trials of IAS

• Mixed cohort, small numbers, limited follow up

2 recent ‘pivotal’ studies:

NCIC PR7, SWOG 9346

• Both started in mid-90’s

• 1386 and 1535 patients

• Long and meticulous follow up

• NCIC PR-7 (Canadian led, with US, UK participation)

– Non-metastatic

– Prior radical therapy with rising PSA

• SWOG 9346 (US, with Canada)

– Bone metastases

• N=1386 • Median F/U 6.9 years (2.8-11.2 years) • 524 deaths (38%)

Pe

rce

nta

ge

0

20

40

60

80

100

Time (Years)

0 696 690

2 652 651

4 561 571

6 319 327

8 125 140

10 35 34

Continuous Intermittent

# At Risk

Overall Survival (ITT)

Hazard Ratio 1.02 (95% CI =0.86 – 1.21)

Test for non-inferiority of HR (IAS vs CAD)≥ 1.25; p-value = 0.009

Study Arm Median (years)

Continuous Androgen Deprivation (CAD) 9.1

Intermittent Androgen Suppression (IAS) 8.8

Mortality by cause (ITT)

Study Arm

PCA deaths

CV/Unknown cause

CAD 87 103

IAS 110 87

Death related to disease IAS CAD

Death non related to disease IAS CAD

Disease-Specific HR: 1.23 87(95%CI = 0.94 – 1.66); p = 0.13

Estim

ate

d C

um

ula

tive

In

cid

en

ce

0.0

0.2

0.4

0.6

0.8

1.0

Time (Years)

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10

NEJM 368;14 april 4, 2013

SWOG 9346 survival: M Hussain,

NEJM 2013 Conclusion: ‘Results inconclusive’

765

770

325

291

64

52

No. at risk

Continuous therapy

Intermittent therapy

70

60

50

40

30

20

10

0 0 5 10 15

Years since randomization

Su

rviv

al

(%)

100

90

80

HR 1.09 (0.95-1.24)

Median No. of survival deaths (years)

Continuous therapy 445 5.8

Intermittent therapy 483 5.1

SWOG 9346 Survival

HR 1.10 (0.99-1.23) NS

Subgroup analysis: SWOG 9346

PSA Response Predicts Survival

PSA at end of 7-month induction period and OS

Hussain M, et al. J Clin Oncol. 2006;24:3984-3990.

PSA, prostate specific antigen; IAD, intermittent androgen deprivation; OS, overall survival; SWOG, Southwest Oncology Group

At

Risk Deaths

Median

in

Months

PSA ≤

0.2 602 199 75

0.2 <

PSA ≤

4.0

360 166 44

PSA >

4.0 383 322 13

P < .0001

Months after end of induction

100

0 24 48 72 96 120 0

20

40

60

80

Author QOL with intermittent vs continuous ADT IAD

better

Calais da

Silva Improved hot flushes, gynecomastia, ED ✔

Crook Improved hot flushes, libido, ED, fatigue, LUTS ✔

De Leval Improved toxicity profile ✔

Hering Improved sexual function ✔

Hussain Improved sexual function, mental health ✔

Irani Improved erectile function ✔

Langenhuijsen Improved hot flushes, nausea, gynecomastia, affect ✔

Miller Improved overall health and sexual function ✔

Mottet Improved side effects (headache, hot flushes) ✔

Salonen Improved activity, physical capacity and sexual. function ✔

Verhagen Improved physical/emotional functional domains ✔

Comparative QOL benefits of Intermittent vs Continuous ADT

Meta-analysis of IAD studies: OS (N=5767) Brungs D et al, Pca and Prost Dis 2014

PFS: No difference CSS: No diff. Non pca mortality: No diff.

Adverse Health Events

Following Intermittent a

nd Continuous ADT in

SWOG 9346.

Hershman D, Hussain M.

JAMA Oncol. 2016 Apr

1;2(4):453-61

•Linked SWOG 9346 to

Medicare data

•10-year cumulative incidence of CV events:

• 24% continuous vs 33% intermittent ADT (HR 0.69; P = .02)

‘Delayed therapy’ vs

intermittent therapy?

• Standard of care is to treat PSA failure before metastatic disease

• Wide range of PSA thresholds for intervention

• ‘Delayed’ does not preclude intermittent once treatment started

Randomized Controlled Trials of

Early vs Deferred Hormonal Therapy

Bolla

Pilepich

Pilepich

MRC

Messing

1997

1997

1997

1997

1999

415

173

938

98

T3Nx

T2 / 3Nx

Gleason 8 - 10

T3 - M +

N +

79 vs 62 %

73 vs 65 %

66 vs 55 %

60 vs 45 %

90 vs 75 %

p < 0.001

p < 0.05

p < 0.05

p < 0.05

p < 0.05

N Stage 5 - year survival P

Studer 2005 985 T0-4 N0 M0 11% OS benefit p< 0.05

(DSS 80 vs 55 %)

Timing of ADT in patients with rising PSA. Duchesne GM

et al, Lancet Oncol. 2016 Jun;17(6):727-3

• First randomized trial of early vs delayed ADT for PSA failure

• 293 men (261 with PSA relapse, 32 primary ADT)

• Randomized between early and delayed ADT.

• 2/3 received intermittent ADT (9 months, retreat when PSA 20)

• Median follow-up 5 yrs

• 5-year OS 86% in delayed vs 91% immediate p=·047

• HR for OS 0·55

• CV AE in 6% delayed vs 9% immediate

PCA complication free Time to ADT in delayed arm

Timing of androgen-deprivation therapy in patients with prostate cancer with a rising

PSA (TROG 03.06 and VCOG PR 01-03 [TOADl Duchesne et al, Lancet Oncol 17: 6, 2016,

727–737

OS HR 0.55, p=.047

IADT: when to consider • In men with biochemical recurrence initiating ADT:

– Good PSA response (< 1.0 ng/mL) within 6 months of ADT

• In men with metastatic disease:

– Excellent PSA response (< 0.2 after 6-8 months)

– Asymptomatic

– NO large vertebral metastases or hydronephrosis

– Resume continuous ADT if rapid early rise in PSA

• Do not consider IADT if:

– Gleason score of 9 - 10

– High burden of metastatic disease or symptoms

– PSA > 100 ng/mL