Upfront DoceTAXel Therapy in Advanced Prostate Cancer: TAXation with or without representation?

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1 Upfront DoceTAXel Therapy in Advanced Prostate Cancer: TAXation with or without representation? Chelsea Minor, Pharm.D. PGY2 Hematology/Oncology Pharmacy Resident South Texas Veterans Health Care System The University of Texas at Austin College of Pharmacy The University of Texas Health Science Center at San Antonio September 9, 2016 Objectives 1. Review epidemiology and pathophysiology of prostate cancer 2. Discuss treatment for metastatic prostate cancer including current standards of care and alternative treatments 3. Review literature regarding the efficacy of initial therapy with docetaxel in patients with metastatic castrate sensitive prostate cancer 4. Provide recommendations for the treatment of patients with metastatic castrate sensitive prostate cancer

2 Incidence Background I. Prostate cancer 1 1. Prostate cancer is a single histological disease with marked clinical heterogeneity 2. Ranges from indolent, clinically irrelevant disease to virulent, rapidly lethal phenotype II. Epidemiology 1. Incidence 2 a. Estimated 180,890 new cases in the United States in 2016 b. Estimated 26,120 deaths in U.S. in 2016 c. Third most common cancer in men d. Fourth leading cause of cancer death e. Increased incidence of metastatic disease since Year Figure 1. Annual incidence of metastatic prostate cancer from Survival 2 a. Local stage (stage I and II) five year survival rate is ~100% b. Regional stage (stages III and IV) five year survival is ~100% c. Distant stage (stage IV with metastases) five year survival rate is 29.3% 3. Etiology 2,4 a. Risk factors i. Age > 50 years ii. Family history iii. African American race b. Associations i. Obesity ii. Geographic location: North America, Northwest Europe, Australia, and Caribbean islands iii. Vasectomy iv. Smoking v. Agent Orange exposure vi. Sexually transmitted infections Minor 2

3 III. Pathophysiology 5,6 1. Cell injury due to various genetic and environmental factors 2. Proliferative inflammatory atrophy (PIA): increased proliferation of gland cells in areas of atrophy 3. Prostatic intraepithelial neoplasia (PIN): presence of abnormal gland cells. Classified as low grade or high grade 4. Unreversed cellular damage can progress to prostate cancer 5. Role of androgens a. Prostate tissue is dependent on androgens for growth and differentiation b. Abnormal tumor cell proliferation is promoted by the presence of androgens c. Androgen synthesis of which is mediated through the hypothalamus, pituitary, adrenal glands, and testes Normal prostate RNASEL, ELAC2, MSR1 germ-line mutations Figure 2. Prostatic inflammation and carcinogenesis 5 PIA PIN Localized disease Metastatic disease GSTP1 hypermethylation 8q gain or loss Decrease in p27 Decrease in NKX3.1 Loss of 10q, 13q, Xq Figure 3. Molecular pathogenesis of prostate cancer 5 Decrease in PTEN Gain at 7p, 7q, Xq Castration resistance AR gene mutation or amplification II. Signs and symptoms 2 1. Early stage is typically asymptomatic 2. Locally advanced patients may present with dysuria or hematuria 3. Advanced stage patients may experience bladder outlet obstruction, impotence, bone pain, lower extremity edema, anemia, or weight loss III. Screening 7 1. Prostate specific antigen (PSA) 2. Digital rectal exam (DRE) Minor 3

4 IV. Diagnosis 7 1. PSA 2. DRE 3. Transrectal ultrasound (TRUS) 4. Prostate MRI 5. Prostate biopsy V. Staging 1. Gleason score 8,9 a. Used to determine the histopathologic morphologic heterogeneity b. Primary, secondary, and tertiary patterns are assigned a pattern number c. Primary and the higher pattern number of either the secondary and tertiary pattern are summed to obtain the final Gleason score d. Scores range from two to ten, with ten being the least differentiated 2. American Joint Committee on Cancer (AJCC) stage 10 (Appendix A) a. Used to determine anatomic stage and prognostic group b. Evaluates size of the tumor, extent of lymph node involvement, and presence of metastases Treatment I. Initial therapy 1. Choice is based on recurrence risk and estimated patient survival 2. Informed patient decision based on risks vs. benefits and personal preferences Table 1. Risk Groups 7 Recurrence Risk AJCC PSA Gleason Clinically localized Very low a T1c < 10 ng/ml b 6 Low T1-T2a < 10 ng/ml 6 Intermediate T2b-T2c or ng/ml 7 High T3a or >20 ng/ml 8-10 Locally advanced Very high T3b-T4 or Primary pattern 5 c Metastatic Any T, N1 or Any T, Any N, M1 a < 3 prostate biopsy cores positive 50% cancer in each core; b PSA density <0.15 ng/ml/g; c Alternatively, > 4 cores with score of 8-10 Clinically localized disease Locally advanced disease Metastatic disease Active surveillance EBRT Brachytherapy Prostatectomy ± PLND ADT EBRT + ADT or ADT Figure 4. Initial treatment algorithm adapted from NCCN guidelines 7 EBRT: external beam radiation therapy; PLND: peripheral lymph node dissection; ADT: androgen deprivation therapy; NCCN: National Comprehensive Cancer Network ADT Minor 4

5 3. Treatment options a. Non-pharmacologic therapy (Appendix B) b. Androgen ablation i. Either surgical castration (i.e. bilateral orchiectomy) or ADT ii. Castration defined as serum testosterone < 50 ng/ml (< 1.7 nmol/l) Table 2. Pharmacologic agents used for androgen ablation 11 Class Drugs Mechanism of action Estrogens DES Estradiol Inhibit release of LHRH from the hypothalamus, suppressing pituitary LH release, and reducing testosterone production LHRH agonists Goserelin Leuprolide Triptorelin Binds to LHRH receptors in pituitary, stimulating LH/FSH release, initially increasing testosterone. Negative feedback down regulates LHRH receptor, decreasing LH/FSH release and testosterone LHRH Degarelix Directly inhibits LHRH receptor in the pituitary, decreasing antagonists Antiandrogens Androgen Synthesis inhibitors Bicalutamide Flutamide Nilutamide Enzalutamide Ketoconazole Corticosteroids Aminoglutethimide Abiraterone LH, and thus testosterone Competitively inhibits DHT and testosterone from binding to androgen receptors in prostate cells Inhibits androgen receptor nuclear translocation, DNA binding, and coactivator mobilization leading to apoptosis Inhibits adrenal androgen production Inhibits CYP17A1, resulting in decreased circulating testosterone DES: Diethylstilbestrol; LH: luteinizing hormone; LHRH: LH-releasing hormone; DHT: dihydrotestosterone c. Toxicities associated with androgen ablation 12 Table 3. Androgen ablation toxicities 12 Hot flashes Anemia Glucose intolerance Cognitive decline Gynecomastia Fatigue Dyslipidemia Depression Osteoporosis Weakness Fat deposition Impotence Hormone- related fractures Gastrointestinal symptoms Muscle wasting 4. Monitoring 7 a. Initial definitive therapy: i. PSA every six to twelve months for five years, then annually ii. DRE annually, unless PSA is undetectable b. Initial N1 or M1 disease: i. Physical exam every three to six months ii. PSA every three to six months Minor 5

6 Figure 5. Natural progression of prostate cancer 13 II. Disease progression 1. Castration resistant prostate cancer (CRPC) 14 a. Progression in the presence of castrate levels of testosterone b. Androgen source that sustains tumor growth gradually moves from endocrine to intratumoral processes and the conversion of adrenal steroid precursors c. Contributing mechanisms of resistance i. Changes in the level of androgen receptor (AR) ligands in tumor tissue ii. Increased protein due to gene amplification or altered mrna expression iii. Activating mutations in the AR that affect structure and function iv. Changes in co-regulatory molecules v. Changes in factors that lead to activation of the receptor independent of the level of ligand or AR allowing kinase cross talk 2. Treatment of CRPC 7 No metastases Metastases Clinical trial (preferred) No visceral metastases Visceral metastases PSADT < 10 mo Secondary ADT 4 PSADT 10 mo Observe Abiraterone + prednisone 1 Docetaxel + prednisone 1 Enzalutamide 1 Radium-223 1,3 Clinical trial Secondary ADT 4 Docetaxel + prednisone 1 Enzalutamide 1 Abiraterone + prednisone Mitoxantrone + prednisone Clinical trial Secondary ADT 4 Keep testosterone < 50 ng/dl Monitor serum PSA Keep testosterone < 50 ng/dl Bone resorptive therapy if bone metastases present Immunotherapy with sipuleucel-t 2 Palliative radiation for bone metastases Best supportive care Figure 6. Initial treatment of CRPC algorithm adapted from NCCN guidelines 7 1NCCN Category 1 recommendation; 2 If minimal or no symptoms, no liver metastases, life expectancy at least six months, 3For symptomatic bone metastases; 4 Secondary ADT: antiandrogen, antiandrogen withdrawal, ketoconazole ± hydrocortisone, corticosteroid, or estrogen therapy; NCCN: National Comprehensive Cancer Network; PSADT: PSA doubling time; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 (Appendix C) Minor 6

7 3. Chemotherapy in mcrpc a. Cytotoxic chemotherapy was largely ineffective in CRPC prior to use of taxanes b. Retrospective review of 957 patients diagnosed with mcrpc between , only 37% of men with mcrpc received docetaxel therapy 15 Table 4. Chemotherapy in mcrpc FDA Approval Regimen Control arm n Outcome 1996 Mitoxantrone + prednisone 16 Prednisone 161 No OS benefit, but improved pain control 2004 Docetaxel + prednisone 17 Mitoxantrone + prednisone 1006 mos: 18.9 vs mo, p=0.009 Docetaxel + estramustine 18 Mitoxantrone + prednisone 770 mos: 17.5 vs mo, p=0.02 OS: overall survival; mos: median overall survival; QOL: quality of life; mo: months 4. Docetaxel 19 a. Cell cycle specific cytotoxic activity b. Exerts mechanism by binding to β-tubulin and stabilizing microtubule polymers which leads to cell cycle arrest and apoptosis c. Toxicities include myelosuppression, alopecia, fluid retention, hypersensitivity reactions, neuropathy 5. Potential barriers of chemotherapy for mcrpc a. Patients are more frail and may have a poor performance status after several lines of therapy b. Pharmacokinetic changes i. Decreased incidence of severe neutropenia in mcrpc patients a. Severe neutropenia in castrate resistant patients: 16-32% b. Severe neutropenia in non-castrate patients: 61-88% ii. Docetaxel clearance increased by approximately 100% in 20 castrated men and associated with a two-fold reduction in area under the curve (p=0.0001) compared to ten non-castrated men 23 iii. No difference in hepatic activity of CYP3A4 between groups (p=0.26) 23 c. Docetaxel resistance 24,25 i. Limiting intracellular drug concentration by efflux pumps ii. Antagonism of drug-stabilizing effect on microtubules iii. Alternative growth pathways or apoptotic escape Minor 7

8 III. Treatment of metastatic castrate sensitive prostate cancer (mcspc) 7 1. Historically treated with surgical castration or ADT 2. Role of chemotherapy in mcspc a. Given earlier to avoid toxicities in older patients with poor performance status b. Potential synergy with androgen deprivation therapy c. Prior studies limited by small sample size and use of chemotherapeutic agents with no proven survival benefit in mcrpc (Table 5) Table 5. Chemotherapy for mcspc Year Agent Intervention Results 1997 Estramustine 26 Orchiectomy alone vs. orchiectomy + EMP (n=419) No OS or PFS benefit. Younger patients with bone metastases did 1997 Epirubicin 27 Epirubicin + ADT vs. ADT alone (n=145) 1999 Mitomycin C 28 Orchiectomy alone vs. orchiectomy + mitomycin C (n=189) 2000 Mitoxantrone 29 Mitoxantrone + ADT vs. ADT alone (n=93) slightly better Improved PFS in men with more than five sites of bony metastases 14 months vs. 9 months (P=0.005) No difference in OS or PFS between groups Improved OS in patients with locally advanced prostate cancer treated with the combination 2004 Estramustine 30 Estramustine + LHRH agonist vs. flutamide + LHRH agonist (n=7) ORR at 12 weeks: 76% vs. 55%; mttp 25.4 vs months 2008 KA/VE 31 ADT vs. KA/VE + ADT (n=286) mttp was 24 vs. 25 months (P=0.39); mos 5.4 vs. 6.1 years (p=0.41) 51% had a grade 3 ADE ORR: overall response rate; mttp: median time to progression; mos: median overall survival; KA/VE: Ketoconazole, doxorubicin, vinblastine, estramustine 3. Rational for taxane therapy in mcspc a. In 2004, docetaxel + prednisone showed an OS benefit in mcrpc 17,18 b. Pre-clinical data showed that in murine models, simultaneous ADT plus paclitaxel was more effective than sequential treatments in delaying time to progression Guideline recommendations Table 6. Current guideline recommendations for docetaxel in mcspc ESMO, July NCCN, March ADT + Docetaxel recommended as first-line treatment of metastatic, hormone-naïve disease in all men fit enough for chemotherapy [1A]. Improved OS was consistent across all subgroups Men with high-volume a, ADT naïve, metastatic disease should be considered for ADT and docetaxel, unless they are non-metastatic or have low-volume disease, since this subgroup was not shown to have improved survival ESMO: European Society for Medical Oncology; NCCN: National Comprehensive Cancer Network ahigh volume disease: visceral disease or four bone lesions with one lesion outside spine or pelvis Minor 8

9 Literature Review Gravis G, Fizazi K, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol 2013; 14: Objective Evaluate the addition of docetaxel to ADT on OS for patients with mcspc Methods Study Design Randomized, open-label, multicenter, phase III trial Population Inclusion Criteria Exclusion Criteria Interventions 18 years Histologically confirmed adenocarcinoma of the prostate Radiologically proven metastatic disease Karnofsky score of 70% (Appendix E) Life expectancy of three months Adequate hematologic, renal, and hepatic function Prior chemotherapy for metastatic disease Progression on prior chemotherapy or ADT ADT therapy started > two months before enrollment Radiotherapy in the prior four weeks Severe cardiac disease Surgical castration prior to metastatic disease occurrence Brain metastasis Peripheral neuropathy ( grade 2) Another cancer diagnosis other than basal or squamous cell skin cancer Randomized in a 1:1 ratio; dynamic minimization used to minimize the imbalance of: prior ADT, chemotherapy for local disease or isolated rising PSA, and Glass risk group (Appendix F) ADT (orchiectomy or LHRH agonist ± non-steroidal antiandrogen) ADT + Docetaxel (Doc) 75 mg/m 2 IV every 21 days, up to nine cycles Premedication: Dexamethasone 8 mg or equivalent on Day 0, 1, 2 Doc could be delayed or dose reduced by up to 25% for toxicity Bisphosphonates allowed Assessments Baseline: Clinical history, weight, Karnofsky PS, and physical exam (PE) Within 30 days of initiation: CT scan, bone scan, electrocardiogram, PSA ADT + Doc: PE and PSA every three weeks during chemotherapy ADT: PE and PSA every three months Imaging every three months, confirmation of radiologic response within a month Quality of life (QOL) questionnaire at initiation, three months, six months, then every six months Endpoints (Appendix D) Statistical Analyses Overall survival (OS) Clinical progression free survival (cpfs) Biochemical progression free survival (bpfs) Intention-to-treat (ITT) for efficacy analysis Population exposed to treatment for safety analysis Sample size of 378 needed to obtain 146 events to detect a hazard ratio (HR) of 0.62 for death with 80% power using a two-sided alpha of 0.05 Post-hoc subgroup analyses Descriptive statistics for baseline characteristics Kaplan-Meier analysis for time to event variables Log-rank test for primary analysis between treatment groups Cox proportional hazards model for adjusted and unadjusted treatment effects Chi-square test for statistical inferences Minor 9

10 Results Enrollment 385 patients between October 2004 and December 2008 at 29 centers in France and one in Belgium ADT + Doc: 192 patients ADT: 193 patients Baseline Characteristics Table 7. Baseline characteristics ADT + Doc (n=192) ADT (n=193) Age (years) Initial Gleason score 8-10, n (%) 103 (55) 113 (59) Metastatic at diagnosis, n (%) 128 (67) 144 (75) Metastatic after localized treatment, n (%) 62 (32) 46 (24) Time from diagnosis to randomization, 2.5 ( ) 2.07 ( ) median [IQR] (mo) Bone metastases, n (%) 155 (81) 156 (81) Lymph node metastases, n (%) 100 (52) 108 (56) Karnofsky score, median [IQR] (%) 100% (90-100) 100% (80-100) Serum PSA, median [IQR] (ng/ml) 26.7 [ ] 25.8 [ ] Glass group, n (%) Good Intermediate Poor 95 (49) 54 (28) 43 (22) Karnofsky score: refer to Appendix E; IQR: interquartile range; Glass group: refer to Appendix F Results Median follow-up: 50 months (IQR 39-63) 96 (50) 57 (30) 40 (21) Table 8. Results ADT + Doc (n=192) ADT (n=193) HR (95% CI) mos, mo (95% CI) 58.9 ( ) 54.2 ( NR) 1.01 ( ) Median cpfs, mo (95% CI) 23.5 ( ) 15.4 ( ) 0.75 ( ) Median bpfs, mo (95% CI) 22.9 ( ) 2.9 ( ) 0.72 ( ) mos: median overall survival; NR: not reached; mo: months; bpfs: biologic PFS; cpfs: clinical PFS) Received nine cycles of Doc: 93 patients (48%) Required dose reduction of Doc due to toxicity: 21 patients (11%) Discontinued Doc due to toxicity: 39/189 patients (21%) High rate of grades 3-4 neutropenia (32%) resulted in amendment requiring granulocyte colony stimulating factor (G-CSF) Post-hoc analysis showed no difference in OS between sub-groups After progression, 62% of the ADT arm and 28% of the Doc +ADT arm went on to receive Doc in the castration resistant setting QOL scores decreased significantly in Doc + ADT arm at three and six month assessment, but mean global functioning scores were similar at 12 months Discussion Critique Strengths Limitations Multicenter, randomized controlled trial (RCT) Long follow-up period Open-label Patients received other treatments after progression, including crossover to docetaxel May have underpowered study based on estimated survival durations Implications Addition of Doc to ADT did not improve OS compared to ADT alone Addition of Doc to ADT did improve cpfs, bpfs, and PSA response High rates of discontinuation due to toxicity, particularly neutropenia Minor 10

11 Sweeney CJ, Chen YH, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. New Engl J Med 2015; 373: Objective Evaluate the ability of early chemotherapy with Doc to improve OS in men initiating ADT for mcspc Methods Study Design Randomized, open-label, multicenter, phase III trial Population Inclusion Criteria Exclusion Criteria 18 years or older Pathological diagnosis of prostate cancer or a clinical scenario consistent with prostate cancer with an elevated PSA Radiologic evidence of extensive metastases (Amended July 2008 to include low volume disease) ECOG PS of 0-2 (Appendix C) ADT< 90 days Adequate organ function Prior adjuvant ADT allowed if duration 24 months AND progression occurred > 12 months after completion of therapy Current ADT for metastatic disease if no evidence of progression and started within 120 days prior to randomization PSA increase > 50% from its lowest point since the beginning of ADT therapy Major surgery within prior four weeks Peripheral neuropathy (> grade 1) Active cardiac disease Palliative RT within 30 days of ADT initiation Interventions Stratified based on age, ECOG PS (Appendix C), planned duration of ADT, use of zoledronic acid (ZA) or denosumab, duration of prior adjuvant ADT, and extent of metastases (High volume defined as visceral disease or four bone lesions with one lesion outside spine or pelvis) ADT alone (LHRH agonist, antagonist, or surgical castration) ADT + Doc 75 mg/m 2 every three weeks for six cycles Premedication: Dexamethasone 8 mg at 12, three, and one hour prior Two dose modifications for toxicity were allowed G-CSF use was at the investigators discretion Use of nonsteroidal antiandrogen was at the investigators discretion Calcium carbonate 500 mg and vitamin D 400 IU by mouth daily Assessments PSA levels, imaging, adverse events ADT: every three months ADT + Doc: every three weeks during treatment, then every three months Endpoints (Appendix D) Statistical Analyses OS Time to CRPC Time to clinical progression (TTP) ITT Sample size adjusted to detect a 33.3% difference in OS between groups with 80% using a stratified log rank test at a one-sided alpha level of 2.5% Sample size was later adjusted based on decision to include patients with low volume disease and again based on new reports of increased OS Interim analyses performed to monitor for futility, with alpha set at nominal one-sided significance level using truncated O Brien-Fleming model Descriptive statistics for baseline characteristics Kaplan-Meier analysis for time to event variables Stratified log-rank test for primary analysis between treatment groups Cox proportional hazards model to estimate HR for time to event variables Fisher s exact test used to compare response rates All P values are two-sided with 95% confidence intervals Minor 11

12 Results Enrollment 790 patients enrolled from July 2006 to December 2012 at 16 centers in the U.S. ADT: 393 patients ADT + Doc: 397 patients Baseline Characteristics Table 9. Baseline characteristics ADT + Doc (n=397) ADT (n=393) Age (years), median Caucasian, n (%) 344 (86.6) 330 (84) ECOG PS (69.8) 272 (69.2) ECOG PS (28.7) 115 (29.3) Low volume metastases, n (%) 134 (33.8) 143 (36.4) High volume metastases, n (%) 263 (66.2) 250 (63.6) Prior prostatectomy, n (%) 81 (20.4) 73 (18.6) Prior radiation, n (%) 27 (6.8) 33 (8.4) No ADT prior to randomization, n (%) 52 (13.2) 51 (12.8) ECOG: Eastern Cooperative Oncology Group (see appendix C); PS: Performance status Results Median follow-up: 28.9 months Table 10. Results ADT + Doc (n=397) ADT (n=393) HR (95% CI) mos, months ( ) High volume, months ( ) Low volume, months NR 0.60 ( ) mttp, months ( ) Time to CRPC, months ( ) PSA response at 1 year, % 27.7% 16.8% p <0.001 mos: median overall survival; mo: months; NR: not reached; mttp: median time to progression; HR: hazard ratio Table 11. Subgroup analyses Subgroups HR (95% CI) ECOG PS ( ) ECOG PS ( ) Visceral metastases ± bone metastases 0.52 ( ) High volume disease with bone metastases alone 0.64 ( ) No prior local therapy 0.66 ( ) Prior local therapy 0.55 ( ) Received six cycles of Doc: 335 patients (86%) Grade 3-4 neutropenia in 12% of Doc + ADT After progression, 47.7% of the ADT arm and 22.7% of the Doc +ADT arm went on to receive Doc in the castration resistant setting Discussion Critique Strengths Limitations Multicenter, RCT Strong internal validity Larger sample size Open-label Large proportion received Doc after disease progression Primarily Caucasian Implications The addition of docetaxel to ADT, improved OS, time to clinical progression, and time to castrate resistance compared to ADT alone OS advantage in subgroup of patients with high volume disease, but not in patients with ECOG of 0, low volume disease, patients with visceral metastases, or those who received previous local therapy Minor 12

13 James ND, Sydes MR, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387 (10024): Objective Evaluate the efficacy of the addition of Doc, ZA, or both to standard of care therapy in patients with advanced prostate cancer Methods Study Design Randomized, open-label, multi-arm, multistage, phase 2/3 clinical trial Population Inclusion Criteria Exclusion Criteria Newly diagnosed prostate cancer either metastatic, node positive, or high risk locally advanced (with two of the following: T3-4, Gleason 8-10, and PSA 40 ng/ml) or relapsed disease with high risk features that was previously treated with radical surgery, radiotherapy, or both ADT started > 12 weeks prior Clinically significant CV history Unfit for chemotherapy Interventions Randomized in a 2:1:1:1 Standard of care: ADT for two years ADT + ZA ADT + Doc ADT + ZA + Doc Assessments Follow-up, PSA, and toxicities Every six weeks for six months, then every 12 weeks for two years, then every six months for five years, then annually Endpoints OS Failure-free survival (FFS) Statistical Analyses ITT analysis Targeted 25% relative improvement in both OS and FFS Required around 400 deaths in the control arm for 90% power and 2.5% onesided alpha accounting for three interim analyses of FFS Maximum family-wise error rate as 6.75% Flexible parametric models and Kaplan Meier used to analyze time to event data Cox proportional hazards regression model used to estimate relative treatment effects, adjusted by stratification factors, and stratified by time periods defined by addition of a new group or end in recruitment to an ongoing group Fine and Gray regression models used for competing risk analysis for survival All tests were two-sided with 95% confidence intervals (CI) Results Enrollment 2962 men from more than 100 sites in the United Kingdom and Switzerland were randomly assigned to four groups between October 2005 and March 2013 ADT (n=1184) ADT+ ZA (n=593) ADT + Doc (n=592) ADT + ZA + Doc (n=593) Minor 13

14 Baseline Newly diagnosed patients: 94% Characteristics Table 12. Baseline characteristics (n=2962) ADT (n=1184) ADT + ZA (n=593) ADT + Doc (n=592) ADT + ZA + Doc (n=593) Age (years) PSA (ng/ml) Orchiectomy, n (%) 5 (0) 4 (1) 2 (0) 3 (1) LHRH based, n (%) 1166 (98) 581 (98) 581 (98) 582 (98) Bicalutamide, n (%) 11 (1) 7 (1) 9 (2) 8 (2) Gleason score 8-10, n (%) 810 (68) 421(71) 436 (74) 425 (72) Metastases, n (%) 724 (61) 366 (62) 362 (61) 365 (62) Bone metastases, n (%) 634 (54) 302 (51) 307 (52) 310 (52) Planned RT, n (%) 340 (29) 172 (29) 168 (28) 170 (29) RT: radiotherapy Results Median follow up: 43 months (IQR 30-60) Table 13. Results (n=2962) ADT (n=1184) ADT + ZA (n=593) ADT + Doc (n=592) ADT + ZA + Doc (n=593) mos, mo [IQR] (HR, 95% CI) 71 [32-NR] NR [32 - NR] (0.94, ) 81 [41 - NR] (0.78, ) 76 [39 - NR] (0.82, ) Five year OS, % Median FFS, mo (HR, 95% CI) (0.92, ) 37 (0.61, ) 36 (0.62, ) Five year FFS, % IQR: interquartile range; NR: not reached; mo: months; OS: overall survival; FFS: failure free survival Table 14. Patients with metastatic disease at baseline (n=1817) ADT (n=724) ADT + ZA (n=366) ADT + Doc (n=362) ADT + ZA + Doc (n=365) mos, mo [IQR] (HR, 95% CI) 45 [23-91] 46 [24 - NR] (0.93, ) 60 [27-103] (0.76, ) 55 [29-99] (0.79, ) Five year OS, % IQR: interquartile range; NR: not reached; mo: months; OS: overall survival; FFS: failure free survival Table 15. Subgroup analyses for OS Subgroups ADT + Doc ADT HR (95% CI) M0 disease 31/230 65/ ( ) M1 disease 144/ / ( ) N0 disease 45/ / ( ) N+ disease 111/ / ( ) Gleason score 7 22/110 76/ ( ) Gleason score / / ( ) Age < 70 years 121/ / ( ) Age 70 years 54/ / ( ) No NSAID/ASA use 125/ / ( ) Either NSAID/ASA use 50/ / ( ) No radiotherapy planned 151/ / ( ) Radiotherapy planned 24/ / ( ) De novo disease 170/564 13/ ( ) Recurrent disease 5/28 65/ ( ) Minor 14

15 Discussion Critique Strengths Limitations Prospective, RCT Strong internal validity Median follow up of 43 months Open-label Only a small proportion of men with recurrent disease Non-standardized 2 nd and 3 rd line therapies Did not define high volume disease Not powered for analysis of subsets with non-metastatic or recurrent disease patients Implications Addition of Doc to SOC improved OS in men with mcspc Cannot generalize results to men with non-metastatic or recurrent disease In addition, no benefit shown in following subgroups: N+ or NX disease, Gleason scores 7, age 70 years, either NSAID/ASA use, or planned radiotherapy Increase in grade 3-5 toxicity with in the first six months, but similar between groups at one year I. Meta-analysis patients included GETUG-AFU, CHAARTED, and STAMPEDE metastatic patients (951 ADT + Doc and 1311 ADT alone) 3. Addition of docetaxel associated improved i. OS (HR 0.73, 95% CI ; p = 0.002) ii. PFS (HR 0.63, 95% CI ; p < 0.001) 4. OS in high vs. low volume disease (CHAARTED and GETUG-AFU 15) i. High volume (HR 0.67, 95% CI ) ii. Low volume (HR 0.80, 95% CI ) 5. No significant heterogeneity amongst the three trials Minor 15

16 Conclusions I. Summary 1. Metastatic prostate cancer is associated with significant morbidity and mortality 2. High proportion of patients with de novo metastatic disease 3. Greater magnitude of OS benefit with docetaxel addition in mcspc, than mcrpc 4. Majority of patients had no major comorbidities (cardiovascular, cerebrovascular, congestive heart failure, diabetes) nor an ECOG PS > 1 5. All three trials showed increased rates of febrile neutropenia with use of docetaxel 6. Benefit most pronounced in certain subgroups: i. Newly diagnosed, metastatic disease ii. High volume disease without visceral metastases II. Recommendations mcspc De novo disease Metastatic disease High volume disease a (without visceral metastases) Low volume disease b Recurrent disease Non-metastatic disease Visceral disease Doc + ADT ADT alone ADT alone Figure 6. Recommendations for initial treatment of mcspc ahigh volume disease: visceral disease or four bone lesions with one lesion outside spine or pelvis blow volume disease: no visceral disease, < four bone lesions or four bone lesions but no lesions outside spine or pelvis III. Future directions 1. Should patients with bulky disease that does not strictly qualify as high-volume disease as defined by CHAARTED standards still be considered for docetaxel therapy? 2. Would younger patients benefit from more aggressive upfront approach regardless of disease volume or presence of poor prognostic factors? 3. Should locally advanced disease receive docetaxel upfront? Minor 16

17 References 1. Small E. Prostate Cancer. In: Goldman L, Ausiello D, eds. CECIL Textbook of Medicine. 22nd ed. Philadelphia: W.B. Saunders Company; American Cancer Society Information and Resources for Cancer: Breast, Colon, Lung, Prostate, Skin. Web. 11 Mar Accessed 21 Aug Weiner AB, Matulewicz RS, Eggener SE, Schaeffer EM. Increasing incidence of metastatic prostate cancer in the United States ( ). Web. 19 July Prostate Cancer Prostatic Dis Accessed 21 August Pienta KJ, Esper PS. Risk factors for prostate cancer. Ann Intern Med. 1993;118(10): Nelson WG, De marzo AM, Isaacs WB. Prostate cancer. N Engl J Med. 2003;349(4): Norris LB, Kolesar JM. Chapter 108. Prostate Cancer. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; Accessed August 21, National Comprehensive Cancer Network. Prostate Cancer (Version ). Accessed 21 Aug SEER Training Modules, Prostate Cancer. U. S. National Institutes of Health, National Cancer Institute. 21 Aug Gleason, D. F. (1977). "The Veteran's Administration Cooperative Urologic Research Group: histologic grading and clinical staging of prostatic carcinoma". In Tannenbaum, M. Urologic Pathology: The Prostate. Philadelphia: Lea and Febiger. pp ISBN X. 10. Edge SB, Byrd DR, Compton CC (eds). AJCC Cancer Staging Handbook, 7 th edition. New York, NY: Springer Denmeade SR, Isaacs JT. A history of prostate cancer treatment. Nat Rev Cancer. 2002;2(5): Kumar RJ, Barqawi A, Crawford ED. Adverse events associated with hormonal therapy for prostate cancer. Rev Urol. 2005;7 Suppl 5:S Ramalingam S, Pollak KI, Zullig LL, Harrison MR. What Should We Tell Patients About Physical Activity After a Prostate Cancer Diagnosis?. Oncology (Williston Park, NY). 2015;29(9):680-5, 687-8, Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 2005;23(32): Zielinski RR, Azad AA, Chi KN, Tyldesely S. Population-based impact on overall survival after the introduction of docetaxel as standard therapy for metastatic castration resistant prostate cancer. Can Urol Assoc J 2014; 8: E Osoba D, Tannock IF, Ernst DS, Neville AJ. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol. 1999;17(6): Tannock IF, De wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15): Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15): Taxotere (docetaxel) [prescribing information]. Bridgewater, NJ: Sanofi-Aventis; December Rathkopf D, Carducci MA, Morris MJ, et al: Phase II trial of docetaxel with rapid androgen cycling for progressive noncastrate prostate cancer. J Clin Oncol 2008: 26: , 21. Hussain A, Dawson N, Amin P, et al: Docetaxel followed by hormone therapy in men experiencing increasing prostatespecific antigen after primary local treatments for prostate cancer. J Clin Oncol 2005: 23: Taplin ME, Xie W, Bubley GJ, et al: Docetaxel, estramustine, and 15-month androgen deprivation for men with prostatespecific antigen progression after definitive local therapy for prostate cancer. J Clin Oncol 2006: 24: , 23. Franke RM, Carducci MA, Rudek MA, Baker SD, Sparreboom A. Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer. J Clin Oncol. 2010;28(30): Galletti E., Magnani, M., Renzulli, M.L., et al. Paclitaxel and docetaxel resistance: molecular mechanisms and development of new generation taxanes. ChemMedChem. 2007;2(7): Seruga, B., Ocana, A., Tannock, I.F. Drug resistance in metastatic castration resistant prostate cancer. Nat Rev Clin Oncol. 2011; 8(1): Janknegt RA, Boon TA, van de Beek C, Grob P. Combined hormono/chemotherapy as primary treatment for metastatic prostate cancer: a randomized, multicenter study of orchiectomy alone versus orchiectomy plus estramustine phosphate. The Dutch Estracyt Study Group. Urology 1997; 49: Pummer K, Lehnert M, Stettner H, Hubmer G. Randomized comparison of total androgen blockade alone versus combined with weekly epirubicin in advanced prostate cancer. Eur Urol 1997; 32: de Reijke TM, Keuppens FI, Whelan P, Kliment J, Robinson MR, Rea LA et al. Orchiectomy and orchiectomy plus mitomycin C for metastatic prostate cancer in patients with poor prognosis: the final results of a European Organization for Research in Cancer Therapy Genitourinary Group Trial. J Urol 1999; 162: Wang J, Halford S, Rigg A, Roylance R, Lynch M, Waxman J. Adjuvant mitozantrone chemotherapy in advanced prostate cancer. BJU Int 2000; 86: Minor 17

18 30. Noguchi M, Noda S, Yoshida M, Ueda S, Shiraishi T, Itoh K et al. Chemohormonal therapy as primary treatment for metastatic prostate cancer: a randomized study of estramustine phosphate plus luteinizing hormone-releasing hormone agonist versus flutamide plus luteinizing hormone-releasing hormone agonist. Int J Urol 2004; 11: Millikan RE, Wen S, Pagliaro LC, Brown MA, Moomey B, Do KA et al. Phase III trial of androgen ablation with or without three cycles of systemic chemotherapy for advanced prostate cancer. J Clin Oncol 2008; 26: Eigl BJ, Eggener SE, Baybik J, Ettinger S, Chi KN, Nelson C et al. Timing is everything: preclinical evidence supporting simultaneous rather than sequential chemohormonal therapy for prostate cancer. Clin Cancer Res 2005; 11: Parker C, Gillessen S, Heidenreich A, Horwich A. Cancer of the prostate: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26 Suppl 5:v Gravis G, Fizazi K, Joly F, Oudard S, Priou F, Esterni B et al. Androgen-deprivation therapy alone or with docetaxel in noncastrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol 2013; 14: Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. New Engl J Med 2015; 373: James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387 (10024): Tucci M, Bertaglia V, Vignani F, et al. Addition of Docetaxel to Androgen Deprivation Therapy for Patients with Hormonesensitive Metastatic Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. 2016;69(4): Oken MM, Creech RH, Tormey DC, et al. (1982). "Toxicity and response criteria of the Eastern Cooperative Oncology Group". Am. J. Clin. Oncol. 5 (6): Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH. The Use of the Nitrogen Mustards in the Palliative Treatment of Carcinoma - with Particular Reference to Bronchogenic Carcinoma. Cancer. 1948;1(4): Glass TR, Tangen CM, Crawford ED, Thompson I. Metastatic carcinoma of the prostate: identifying prognostic groups using recursive partitioning. J Urol. 2003;169(1): Minor 18

19 Appendices Appendix A. AJCC staging system 10 Primary tumor (T) Pathologic (pt) TX Primary tumor cannot be assessed pt2 Organ confined T0 No evidence of primary tumor pt2a Unilateral, involving one-half of one side or less T1 Clinically apparent tumor neither palpable nor visible by imaging pt2b Unilateral, involving more than one-half of one side but not both sides T1a Tumor incidental histologic finding in 5% or less of pt2c Bilateral disease tissue resected T1b Tumor incidental histologic finding in more than pt3 Extra-prostatic extension 5% of tissue resected T1c Tumor identified by needle biopsy pt3a Extra-prostatic extension or microscopic invasion of bladder neck T2 Tumor confined within prostate pt3b Seminal vesicle invasion T2a Tumor involves one-half of one lobe or less pt4 Invasion of bladder, rectum T2b Tumor involves more than one half of one lobe but not both lobes T2c Tumor involves both lobes T3 Tumor extends through prostatic capsule T3a Extracapsular extension (unilateral or bilateral T3b Tumor invaded seminal vesicle(s) T4 Tumor is fixed or invades adjacent structures other than seminal vesicles: bladder, levator muscles, and/or pelvic wall Regional lymph notes (N) Pathologic (pn) NX Regional lymph nodes not assessed pnx Regional nodes not sampled N0 No regional lymph node metastasis pn0 No positive regional nodes N1 Regional lymph node metastasis pn1 Metastasis in regional node(s) Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis M1a Non-regional lymph node(s) M1b Bone(s) M1c Other site(s) ± bone disease Appendix B. Non-pharmacologic therapy 7 Active surveillance Active monitoring course of disease with expectation to deliver curative therapy on progression (i.e. watchful waiting) EBRT Radiation of the prostate gland from outside the body and can be curative in early stages Brachytherapy Involves placing radioactive sources into prostate tissue at either low or high dose-rates Radical prostatectomy Surgical resection of the prostate. Appropriate if clinically localized to prostate, but usually reserved for patients with a life expectance 10 years PLND Use based on probability of nodal metastases. Extended technique preferred. EBRT: external beam radiation therapy; PLND: pelvic lymph node dissection Appendix C. ECOG PS Criteria 38 Score Criteria 0 Fully active, able to carry on all pre-disease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of light or sedentary nature (e.g. light house work, office work) 2 Ambulatory and capable of all self-care but unable to carry out work activities. Up and about more than 50% of waking hours 3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 Completely disabled cannot carry on any self-care. Totally confined to bed or chair 5 Dead ECOG: Eastern Cooperative Oncology Group; PS: performance status Minor 19

20 Appendix D. Terms used in oncology studies Overall response rate (ORR) Overall survival (OS) Biochemical PFS (bpfs) Clinical PFS (cpfs) Failure free survival (FFS) Time to castration resistance Time to clinical progression Objective response means either a partial or complete response Time from randomization until death from any cause Time to PSA progression, biochemical progression or death Time to clinical progression or death Biochemical failure (rise of 50% above the within-24-week nadir and above 4 ng/ml and confirmed by retest or treatment), progression, or death from prostate cancer Time until documented clinical or serologic progression with a testosterone level of < 50 ng/dl (or source documentation of medical or surgical castration) Time until increasing symptoms of bone metastases, progression according to RECIST, version 1.0, or clinical deterioration due to cancer according to the investigator s opinion Appendix E. Karnofsky scale 39 (recipient age 16 years) Score Criteria Able to carry on normal activity; no special care is needed 100 Normal; no complaints; no evidence of disease 90 Able to carry on normal activity; minor signs or symptoms of disease 80 Normal activity with effort; some signs or symptoms of disease. Unable to work, able to live at home, cares for most personal needs, varying amount of assistance needed 70 Cares for self; unable to carry on normal activity or to do active work. 60 Requires occasional assistance, but is able to care for most of their personal needs. 50 Requires considerable assistance and frequent medical care. Unable to care for self, requires equivalent of institutional or hospital care, disease may progress rapidly 40 Disabled; requires special care and assistance. 30 Severely disabled; hospital admission is indicated although death not imminent. 20 Very sick; hospital admission necessary; active supportive treatment necessary. 10 Moribund; fatal processes progressing rapidly. Appendix F. Glass risk groups for mcspc 40 Prognosis Good Intermediate Criteria No appendicular disease + no visceral involvement OR Appendicular disease ± visceral involvement + PS 0 + Gleason < 8 Appendicular disease ± visceral involvement + PS 0 + Gleason 8 OR Appendicular disease ± visceral involvement + PS 1 + PSA < 65 ng/ml Poor Appendicular disease ± visceral involvement + PS 1 and PSA 65 ng/ml Appendicular disease: bone lesions in the chest, head ± extremities Minor 20

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