Ti Timi ming of ADT T and ch chemotherapy Thomas Keane M.D. Medical University of South Carolina. Charleston S.C.
Conflicts • Tolmar, Ferring, Jannsen, Bayer.
2018 CRPC Treatment Options • Agonists/Antagonists/Orchiectomy • Androgen pathway targeting – Apalutamide (anti-androgen) − Abiraterone (androgen biosynthesis inhibitor) − Enzalutamide (anti-androgen) • Radiopharmaceuticals − Radium 223 • Immunotherapy − Sipuleucel-T • Chemotherapy − Docetaxel (1 st line) − Cabazitaxel (2 nd line) − IS EARLIER BETTER? . − IF SO . USA Today
New concept • could these agents be applied to Hormone Sensitive Prostate Cancer a • Which agents and when ??
Discus ussion n Topi pics • 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
E3805 CHAARTED: ChemoHormonal Therapy vs. Androgen Ablation for Metastatic Prostate Cancer Evaluate every 3 weeks while ARM A: STRATIFICATION receiving ADT + Docetaxel docetaxel and at 75mg/m2 every 21 Extent of Mets week 24 then days for maximum 6 - High vs Low R Follow for time to every 12 weeks cycles Age A progression and ≥70 vs < 70yo N overall survival Original design n=568 for high volume disease • ECOG PS D Adjustments for allowance of low volume • - 0-1 vs 2 Chemotherapy at O disease and projected OS based on S9346 data CAB> 30 days investigator’s M n=780 -Yes vs No discretion at I SRE Prevention progression ARM B: Z -Yes vs No Evaluate every ADT (androgen E Prior Adjuvant ADT 12 weeks deprivation therapy ≤12 vs > 12 months alone) • ADT allowed up to 120 days prior to randomization • Intermittent ADT dosing was not allowed Sweeney C et al. ASCO 2014; Abstract LBA2. • Standard dexamethasone premedication but NO DAILY PREDNISONE
E3805 CHAARTED: ChemoHormonal Therapy vs. Androgen Ablation for Metastatic Prostate Cancer 1.0 • N=790 men accrued 07/28/06 - Primary endpoint – 0.9 11/21/12 Overall survival 0.8 • Planned interim analysis at 53% information met 10/13 0.7 • 01/16/14 median followup 29 0.6 months 0.5 Probability 136 (110 high volume) deaths • HR=0.61 (0.47-0.80) 0.4 p=0.0003 ADT alone vs. 101 (82 high 0.3 Median OS: volume) deaths ADT+D ADT + D: 57.6 months 0.2 • 83.6% vs. 83.2% of deaths ADT alone: 44.0 months from prostate cancer 0.1 0.0 0 12 24 36 48 60 72 84 OS (Months) Sweeney C et al. ASCO 2014; Abstract LBA2.
E3805 CHAARTED: ChemoHormonal Therapy vs. Androgen Ablation for Metastatic Prostate Cancer OS by extent of metastatic disease at start of ADT 1.0 1.0 >4 bone lesions and >1 lesion in any bony structure 0.9 0.9 beyond the spine/pelvis 0.8 0.8 OR visceral disease 0.7 0.7 0.6 0.6 0.5 0.5 Probability Probability p=0.1398 p=0.0006 0.4 HR=0.63 (0.34-1.17) 0.4 HR=0.60 (0.45-0.81) Median OS: Median OS: 0.3 0.3 ADT + D: Not reached ADT + D: 49.2 months ADT alone: Not reached 0.2 ADT alone: 32.2 months 0.2 0.1 0.1 0.0 0.0 0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84 Low volume High volume OS (Months) OS (Months) Sweeney C et al. ASCO 2014; Abstract LBA2. Arm TOTAL DEAD ALIVE MEDIAN
CHAARTE TED -4 Y 4 YEAR ME MEDIAN F N FOLL LLOW U UP • Median OS- 57.6 chemohormonal VS 47.2 mts ADT alone. HR 0.72. p=0.0018, • High- Vol DZ (513) 51.2 VS 34.4 mts , • Mortality Risk Reduction- 36% p=0.001, • Median Overall survival benefit from chemotherapy was 16.8 mts , • Low volume disease - no evidence of improved survival when docetaxel was added, • Prior local therapy: Docetaxel –no survival benefit in low volume pts but a non significant survival benefit was reported in the high volume subgroup (median survival)- 66.9 vs 51.7 mts . • Results - benefit was more evident in high vs low volume subgroups and burden of metastases determined by conventional imaging may help select pts for this strategy. J Clin Oncol 75.3657.2018
STAMPEDE: Docetaxel and/or Zoledronic Acid in Hormone-Naive Metastatic PCa First overall survival analysis of patients enrolled in the following 4 study arms: • Standard of care (SOC; n = 1,184) • Zoledronic acid (ZDA) + SOC (n = 593) • Docetaxel (Doc) + SOC (n = 592) • Doc + ZDA + SOC (n = 593) SoC Doc + SoC ZDA + SoC Doc + ZDA + SoC Median overall survival 67 mo 77 mo 80 mo 72 mo Hazard ratio ( p -value) Ref* 0.76 (0.003) 0.93 (0.44) 0.81 (0.02) Median failure-free 21 mo 37 mo 21 mo 37 mo survival Hazard ratio ( p -value) Ref* 0.62 (<0.1 x 10 -10 ) 0.93 (0.26) 0.62 (<0.1 x 10 -10 ) * Pairwise comparisons to control SOC study arm were calculated for each research arm. • Docetaxel, and not ZDA, improves overall survival compared to SoC • Docetaxel + ZDA improves survival but offers no obvious benefit over docetaxel alone James ND et al. Proc ASCO 2015;Abstract 5001.
HR=1.01 (0.75-1.36) HR=0.72 (0.57-0.91) p=0.955 p=0.005 Median OS: Median OS: ADT + D: 58.9 months ADT + D: 22.9 months ADT alone: 54.2 months ADT alone: 12.9 months Overall Survival Biochemical PFS Gravis et al. Lancet Oncol. 2013; 14:149-58.
Key Differences between GETUG-AFU 15 and CHAARTED GETUG-15 CHAARTED N 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) 1. Glass TR et al. J Urol 2003; 169:164-9; 2. Eisenberger M et al. N Engl J Med 1998; 339:1036-42; 3. Millikan RE et al. J Clin Oncol 2008; 26: 5936-42.
Summary y of Factors that may y have Con Contributed t to D o Different R Results b between GETUG-AF GE AFU 15 a U 15 and CHAAR CHAARTE TED • 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
Gr Grade 3 3-5 5 Hematologic Toxicity y from TAX327 327 in mC mCRPC PC vs vs. GET ETUG UG-AFU U 15 vs. CHAARTED ED 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 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; 351:1502-12.
Pharmacokinetics • Franke, RM et al. examined the relative clearance of docetaxel in 10 non-castrated and 20 castrated men with prostate cancer. • Docetaxel pharmacokinetics were significantly altered in the castrated men with an approximately 100% increase in docetaxel clearance and accordingly two-fold reduction in AUC as compared to the men who were not castrated. • Human and rat-model data were presented to suggest a mechanism for this difference in clearance as increased hepatic uptake of docetaxel via increased anion transporter expression in the setting of castration. (8) • There has been suggestion in CHAARTED/STAMPEDE of greater toxicity with Docetaxel in the castration sensitive state but perhaps greater drug exposure also suggests potential for greater efficacy.
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; 28:4562-67; *Bruno R et al. J Clin Oncol 1998; 16:187-96.
What are the Implications of these PK Difference ces? 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?
Qu Question on ? ? • If toxicity is greater with the use of Docetaxol in the pre- castrate state might not efficacy also be ? • We need a trial.
ore Medical But What About Docetaxel Be Befor Castration? The Rationale???? Does one exist
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