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Best of ASCO GU Session

Best of ASCO GU Session. Sandy Srinivas.MD Stanford University. Outline.

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Best of ASCO GU Session

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  1. Best of ASCOGU Session Sandy Srinivas.MD Stanford University

  2. Outline • Abstract #4:Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): Results of S9346 (INT-0162), an international phase III trial. (M. Hussain) • Abstract #LBA4518: Interim analysis results of COU-AA-302, a randomized, phase III study of abiraterone acetate in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC). (C. J. Ryan) • Abstract #LBA4512: Final overall survival analysis results from the phase III, double-blind, randomized, multinational study of radium-223 chloride in the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases (ALSYMPCA). (C. Parker) • Abstract #4519: Primary, secondary, and quality-of-life endpoint results from the phase III AFFIRM study of MDV3100, an androgen receptor signaling inhibitor. (J. S. De Bono) • Abstract #CRA4501:Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Results from a phase III randomized, open-label, multicenter trial. (R. J. Motzer)

  3. Prostate Cancer

  4. SWOG 9346 trial Armstrong, Oncologist 2009

  5. Intermittent versus Continuous Androgen Deprivation in Hormone Sensitive Metastatic Prostate Cancer Patients: Results of SWOG 9346 (INT-0162) an International Phase III Trial Primary Determine if survival with IAD is Not Inferior to survival with CAD. QOL*: To compare 3 treatment-specific symptoms (Impotence, Libido, Energy/Vitality) and physical and emotional functioning between arms- Abstract # 4571

  6. Rationale for Intermittent Therapy • ADT has side effects • Hormonal Therapy in the recurrent state is non curative • Possibility of delaying “Castrate Resistance” • Widely adopted • Differing schedules of start /stop times

  7. Intermittent Androgen Deprivation Adapted Oh ASCO 2012;

  8. NCIC PR7: Intermittent vs. Continuous Androgen Suppression • Median follow-up: 6.9 yrs • Patients had RT and rise in PSA • IAS noninferior to CAD by statistical criteria • OS HR: 1.02 (95% CI: 0.86-1.21) • P for noninferiority (HR ≥ 1.25) = .009 • Time to hormone-refractory state improved with IAS vs. CAD • HR: 0.80 (95% CI: 0.67-0.98; P = .024) • No difference in AEs between arms, except for fewer hot flashes with IAS • Includes similar incidence of myocardial events and osteoporotic fractures Crook, ASCO 2011

  9. Study Design Induction Registration Newly diagnosed metastatic prostate cancer & a PSA  5 ng/mL STEP 1 Induction AD = Goserelin + Bicalutamide X 7 months If PSA  4 ng/mL on months 6&7 (PSA normalization criteria) STEP 2 Randomly Assign Continuous AD Intermittent AD Discontinue AD, monthly PSAs. Resume AD based on pre-specified criteria

  10. Statistical Methods • Primary outcome: Survival post-randomization • Hypothesis: “IAD is NOT inferior to CAD” • Design specifications: • Survival with IAD is not inferior if the 95% confidence interval for the hazard ratio (IAD vs. CAD) excludes 1.2,α=0.05, power=90%, adjusting for stratification factors in proportional hazards model. • Assumptions: post-randomization median survival for CAD = 3 years: • Sample size: 1500 eligible, randomized patients • accrual: 6.25 yrs. + 2 additional yrs. of follow-up.

  11. Overall Survival: Intermittent Therapy is Inferior Compared to Continuous Therapy Median in Years At Risk Death 100% Continuous therapy 765 422 5.8 Intermittent therapy 770 455 5.1 80% 60% 40% 20% 0% 0 5 10 15 Years from Randomization 7 yr Survival 42% 38% HR: 1.09 95% CI (0.95, 1.24) At risk Intermittent 267 47 Continuous 301 53 PRESENTED BY: Maha Hussain, MD, FACP

  12. Results- Subgroup Analysis

  13. Authors Conclusions In this international phase III trial in patients with metastatic hormone sensitive prostate cancer : • IAD was inferior to CAD based on our pre-specified definition of survival comparability [HR: 1.09, 95% CI (0.95, 1.24)]. Therefore, CAD continues to be the standard of care. • In a secondary analysis: • IAD was not-inferior to CAD in patients with extensive disease. [HR: 0.96 95% CI (0.80, 1.16)]. • IAD was inferior in patients with minimal disease & CAD was statistically significantly superior [HR: 1.23, 95% CI (1.02, 1.49), p=0.034].

  14. ( HR: 1.09 95% CI (0.95, 1.24) Superiority: Detects a difference between 2 drugs Equivalence: confirms absence of significant difference between 2 drugs Non Inferior: New Rx is no worse than active by a prespecified amount

  15. Conclusions • Authors were unable to show that IAD was no worse than CAD ( Did not prove that CAD is superior) • Improvement in QOL with impotence, libido and E/V with IAD • Accrual was twice as long as planned (6 vs 13 yrs) • Subgroup of extensive vs minimal was not preplanned • NCIC was in non metastatic (which is minimal ds) • Patients should be counseled about risks and benefits of any therapy • IAD remains a reasonable option for patients with both PSA alone ds and those with metastases

  16. COUGAR Armstrong, Oncologist 2009

  17. Interim Analysis: a Randomized, Phase 3 Study of Abiraterone Acetate in Chemotherapy-Naïve Patients With mCRPC OS Benefit Shown in Post-Chemotherapy mCRPC Patients- FDA apprved 4/2011Median Survival was 14.8 monthsImprovement of 3.9 months over Prednisone control arm

  18. Overall Study Design of COU-AA-302 RANDOMIZED 1:1 Efficacy end points • Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada • Stratification by ECOG performance status 0 vs 1 Patients AA 1000 mg daily Prednisone 5 mg BID (Actual n = 546) • Co-Primary: • rPFS by central review • OS • Secondary: • Time to opiate use (cancer-related pain) • Time to initiation of chemotherapy • Time to ECOG-PS deterioration • TTPP • Progressive chemo-naïve mCRPC patients(Planned N = 1088) • Asymptomatic or mildly symptomatic Placebo daily Prednisone 5 mg BID (Actual n = 542)

  19. COU-AA-302 Statistical Plan Planned OS Analysis 1Q10 2Q10 3Q10 4Q10 1Q11 2Q11 3Q11 4Q11 1Q12 2Q12 3Q12 4Q12 IA1 (~15% OS Events) 116 Events  < 0.0001 IA2 (40% OS Events) 311 Events  = 0.0005 IA3 (55% OS events) 425 Events  = 0.0034 IA = interim analysis. Ho, HR=1.0.

  20. Statistically Significant Improvement in rPFS Primary End Point 100 80 60 Progression-Free (%) 40 20 AA + P PL + P 0 3 6 9 12 15 18 0 Time to Progression or Death (Months) AA PL 546 542 489 400 340 204 164 90 46 30 12 3 0 0 Data cutoff 12/20/2010. NR, not reached; PL, placebo.

  21. Strong Trend in OS Primary End Point 100 80 60 Survival (%) 40 20 AA + P PL + P 0 3 6 9 12 15 18 21 24 27 30 33 0 Time to Death (Months) 546 542 538 534 524 509 503 493 482 465 452 437 412 387 258 237 120 106 27 25 0 2 0 0 AA PL Data cutoff 12/20/2011. Pre-specified significance level by O’Brien-Fleming Boundary = 0.0008.

  22. rPFS Benefit Demonstrated Across Full Spectrum of Patient Subgroups FavorsAA FavorsPlacebo Median (months) Variable Subgroup HR 95% CI AA Placebo All subjects Baseline ECOG Baseline BPI Bone metastasis only at entry Age Baseline PSA above median Baseline LDH above median Baseline ALK-P above median Region ALL 0 1 0-1 2-3 YES NO < 65 ≥ 65 ≥ 75 YES NO YES NO YES NO N.A. Other NE 13.7 NE NE 11.1 NE 11.3 13.7 NE NE 11.9 NE NE NE 11.5 NE NE 11.5 8.3 8.3 7.4 8.4 8.2 13.7 5.6 5.6 9.7 11.0 8.0 8.5 5.6 9.0 8.2 8.3 8.2 8.4 0.43 0.45 0.35 0.42 0.51 0.48 0.38 0.36 0.45 0.57 0.44 0.40 0.37 0.48 0.50 0.34 0.36 0.52 (0.35-0.52) (0.36-0.57) (0.23-0.54) (0.32-0.54) (0.35-0.75) (0.34-0.69) (0.30-0.49)(0.25-0.53)(0.35-0.58)0.39-0.83)(0.33-0.58) (0.29-0.54) (0.28-0.49) (0.36-0.65) (0.38-0.66) (0.25-0.47) (0.27-0.48) (0.39-0.69) 0.2 0.75 1 1.5

  23. Serologic and Clinical Responses

  24. Adverse Events Most ALT and AST increases occurred during the first 3 months of treatment

  25. Conclusions • Authors: In patients with asymptomatic and mildly symptomatic, chemotherapy-naïve mCRPC, treatment with abiraterone acetate plus prednisone: • Delays disease progression • Increases survival • Extends time with minimal or no symptoms • No new important safety signals • Valuable drug; Will become a standard pre chemotherapy • Approval pending • Earlier closure will not impact clinical use

  26. ALMSYMCA AFFIRM Armstrong, Oncologist 2009

  27. Phase 3 Trial (AFFIRM) of (MDV3100), an Androgen Receptor Signaling Inhibitor: Primary, Secondary, and QOL Results Chemo-naïve (n = 65) Post-chemo (n = 75) Chemo-naïve (n = 65) Tran C, et al. Science. 2009;324:787-790.

  28. AFFIRM Trial Design RANDOMIZED 2:1 Patient Population: 1199 patients with progressive CRPC * Failed docetaxel chemotherapy Enzalutamide 160 mg daily n = 800 Primary Endpoint: Overall Survival Placebo n = 399 Glucocorticoids were not required but allowed. PCWG2 criteria used (continue therapy through minor PSA changes; confirm bone scan ‘progression’; focus on benefit not response).* Recruitment in 156 centers from 15 countries and 5 continents. Enrollment between September 2009 and November 2010. * Scher et al, 2008

  29. End Points • Primary endpoint: Overall survival • Stratification variables: • ECOG Performance Status (0-1, 2) • Mean Brief Pain Inventory Q#3 Score (<4, ≥ 4) • Statistical design: • Cumulative alpha: 0.05 (2-sided) • Power: 90% to detect a 24% reduction in mortality (target HR = 0.76) • One planned interim analysis at 520 events Secondary Endpoints: Response Indicators • PSA Response • Soft Tissue Objective Response • FACT-P Quality of Life • Pain Palliation • Circulating Tumor Cells Progression Indicators • Time to PSA Progression • Radiographic Progression-free Survival • Time to First Skeletal-Related Event

  30. Enzalutamide Prolonged Survival, Reducing Risk of Death HR = 0.631 (0.529, 0.752) P <0.0001 37% reduction in risk of death Enzalutamide: 18.4 months (95% CI: 17.3, NYR) Placebo: 13.6 months (95% CI: 11.3, 15.8)

  31. Survival Benefit Across All Subgroups Hazard Ratio for Death (95% CI) Overall Survival median (mo) Enzalutamide / Placebo Favors Enzalutamide* Favors Placebo* *Based on data analysis cutoff date for the planned interim analysis.

  32. Enzalutamide had a high PSA Response Rate >50% confirmed PSA fall: Enza 54% ; Placebo 2% (p<0.0001) >90% confirmed PSA fall: Enza 25%; Placebo 1% (p<0.0001) Placebo Enzalutamide All the secondary endpoint measures favored the treatment arm

  33. PSA Progression Free Survival HR = 0.248 P <0.0001 Enzalutamide: 8.3 months (95% CI: 5.8, 8.3) Placebo: 3.0 months (95% CI: 2.9, 3.7) PSA progression defined by PCWG2 criteria

  34. Enzalutamide RECIST Response Rate Enzalutamide (n= 446); placebo (n= 208) with measurable disease Response categories defined by RECIST 1.1

  35. Time to First Skeletal Related Event HR = 0.621 P <0.0001 Enzalutamide: 16.7 months (95% CI: 14.6, 19.1) Placebo: 13.3 months (95% CI: 5.5, NYR)

  36. Quality-of-Life Responses by FACT-P *Response is defined as 10-point increase in the overall score (Cella, 2009).

  37. Adverse Events *AEs graded for severity; grades 1 and 2 milder and grades 3-5 more severe

  38. Adverse Events of Special Interest *Includes terms hyperbilirubinaemia, AST increased, ALT increased, LFT abnormal, transaminases increased, and blood bilirubin increased.

  39. Conclusions • Authors: Enzalutamide, a once a day oral Androgen Receptor Signaling Inhibitor, is well tolerated and prolongs survival in men with CRPC by almost 5 months. • Probably will be used post chemo now and abiraterone will be used pre chemo • Optimum sequence unknown

  40. Zytiga MDV3100 Armstrong, Oncologist 2009

  41. Phase III of radium‑223 chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA) Range of alpha-particle Radium-223 Bone surface

  42. ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design STRATIFICATION PATIENTS TREATMENT 6 injections at 4-week intervals • Confirmed symptomatic CRPC • ≥ 2 bone metastases • No known visceral metastases • Post-docetaxel or unfit for docetaxel R AND OMI S ED Radium-223 (50 kBq/kg) + Best standard of care • Total ALP: < 220 U/L vs ≥ 220 U/L • Bisphosphonate use: Yes vs No • Prior docetaxel: Yes vs No Placebo (saline) + Best standard of care 2:1 N = 921 Planned follow-up is 3 years

  43. ALSYMPCA Updated AnalysisOverall Survival 100 HR = 0.695 95% CI, 0.581, 0.832P = 0.00007 90 80 70 60 50 % Radium-223, n = 614 Median OS: 14.9 months 40 30 20 Placebo, n = 307 Median OS: 11.3 months 10 0

  44. ALSYMPCA Updated AnalysisSurvival Benefit Across Patient Subgroups

  45. ALSYMPCA Updated AnalysisAEs of Interest

  46. ALSYMPCA Updated Analysis OS by Stratification Variables: Prior Docetaxel Use Prior docetaxel use NO prior docetaxel use 100 100 HR = 0.710 95% CI, 0.565, 0.891P = 0.00307 HR = 0.745 95% CI, 0.562, 0.987P = 0.03932 90 90 80 80 70 70 60 60 % % 50 50 Radium-223, n = 352 Median: 14.4 months Radium-223, n = 262 Median: 16.1 months 40 40 30 30 20 20 Placebo, n = 133 Median: 11.5 months Placebo, n = 174 Median: 11.3 months 10 10 0 0 Month Month 16 24 0 0 4 4 8 8 12 12 16 20 20 24 28 32 28 32 36 40 36

  47. ALSYMPCA Updated Analysis Time To First SRE* 100 HR = 0.64 95% CI, 0.52, 0.78P < 0.0001 90 80 70 60 Radium-223, n = 614 Median: 12.2 months 50 % 40 Placebo, n = 307 Median: 6.7 months 30 20 10 0 *Provisional data

  48. ALYSMPCA Updated Analysis Conclusions • Radium-223 compared with placebo in CRPC patients with bone metastases: • Significantly prolonged median OS by3.6 months Significantly prolonged median time to first SRE by 5.5 months My Comments: • Useful drug in patients with significant pain • Only bone metastases/not visceral disease • Post docetaxel/docetaxel ineligible patients • Nuclear Medicine Referral

  49. Renal Cell Carcinoma

  50. Current State & Challenges in mRCC • Explosion of choices in the last 7 years • 8 FDA approved agents yet median OS still ~2 years • Few cures • Efficacy at the expense of toxicity • Limited selection and prediction criteria

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