Intermittent Androgen Deprivation Therapy (ADT): Benefits outweigh risks

Transcription

1 Intermittent Androgen Deprivation Therapy (ADT): Benefits outweigh risks Laurence Klotz Professor of Surgery Sunnybrook Health Sciences Centre University of Toronto

2 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

3 Sex Steroids as Tumor Suppressors in Breast and Prostate Cancer

4 Actuarial survival of intermittent bicalutamide (AA) monotherapy verses LHRH agonist +/- AA (Int LHRH) Oliver T, FOIUS P= Years AA Int LHRH

5 Earlier Phase 3 Trials of IAS 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 Mixed cohort, small numbers, limited follow up

6 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

7 N=1386 Median F/U 6.9 years ( years) 524 deaths (38%)

8 Percentage Overall Survival (ITT) Study Arm Median (years) Continuous Androgen Deprivation (CAD) 9.1 Intermittent Androgen Suppression (IAS) 8.8 Hazard Ratio 1.02 (95% CI = ) Test for non-inferiority of HR (IAS vs CAD) 1.25; p-value = # At Risk Continuous Intermittent Time (Years)

9 Estimated Cumulative Incidence Mortality by cause (ITT) 1.0 Study Arm PCA deaths CV/Unkno wn cause 0.8 CAD IAS Disease-Specific HR: (95%CI = ); p = Death related to disease Death non related to disease IAS CAD IAS CAD Time (Years)

10 NEJM 368;14 april 4, 2013

11 Survival (%) SWOG 9346 survival: M Hussain, NEJM 2013 Conclusion: Results inconclusive No. at risk Continuous therapy Intermittent therapy HR 1.09 ( ) Years since randomization Median No. of survival deaths (years) Continuous therapy Intermittent therapy

12 SWOG 9346 Survival HR 1.10 ( ) NS

13 Subgroup analysis: SWOG 9346

14 PSA Response Predicts Survival PSA at end of 7-month induction period and OS PSA < PSA 4.0 PSA > 4.0 At Risk Deaths Median in Months P < Months after end of induction PSA, prostate specific antigen; IAD, intermittent androgen deprivation; OS, overall survival; SWOG, Southwest Oncology Group Hussain M, et al. J Clin Oncol. 2006;24:

15 Comparative QOL benefits of Intermittent vs Continuous ADT 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

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

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

18 Adverse Health Events Following Intermittent a nd Continuous ADT in SWOG Hershman D, Hussain M. JAMA Oncol Apr 1;2(4): Linked SWOG 9346 to Medicare data 10-year cumulative incidence of CV events: 24% continuous vs 33% intermittent ADT (HR 0.69; P =.02)

19 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

20 Randomized Controlled Trials of Early vs Deferred Hormonal Therapy Bolla Pilepich N Stage T3Nx T2 / 3Nx 5 - year survival 79 vs 62 % 73 vs 65 % P p < p < 0.05 Pilepich 1997 Gleason vs 55 % p < 0.05 MRC T3 - M + 60 vs 45 % p < 0.05 Messing N + 90 vs 75 % (DSS 80 vs 55 %) p < 0.05 Studer T0-4 N0 M0 11% OS benefit p< 0.05

21 Timing of ADT in patients with rising PSA. Duchesne GM et al, Lancet Oncol 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

22 Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG and VCOG PR [TOADl Duchesne et al, Lancet Oncol 17: 6, 2016, OS HR 0.55, p=.047 PCA complication free Time to ADT in delayed arm

23 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