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Enhancing Treatment Experiences in Castration-Resistant Prostate Cancer: The Nurse's View


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Enhancing Treatment Experiences in Castration-Resistant Prostate Cancer: The Nurse's View

  1. 1. Enhancing Treatment Experiences in Castration-Resistant Prostate Cancer: The Nurse’s View Brenda Martone, MSN, ANP-BC, AOCNP® Nurse Practitioner Northwestern Medicine
  2. 2. Provided by i3 Health ACCREDITATION i3 Health is accredited with distinction as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. A maximum of 1.0 contact hour may be earned by learners who successfully complete this continuing nursing education activity. INSTRUCTIONS TO RECEIVE CREDIT An activity evaluation form has been distributed. To claim credit, you must turn in a completed and signed evaluation form at the conclusion of the program. Your certificate of attendance will be mailed or emailed to you in approximately 2 weeks. UNAPPROVED USE DISCLOSURE This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. DISCLAIMER The information provided at this CNE activity is for continuing education purposes only and is not meant to substitute for the independent medical/clinical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. COMMERCIAL SUPPORT This activity is supported by independent educational grants from Bayer Healthcare Pharmaceuticals and Sanofi/Genzyme.
  3. 3. Disclosures Brenda Martone, MSN, ANP-BC, AOCNP® discloses the following commercial relationships: Speakers’ bureau: Astellas and Pfizer
  4. 4. Learning Objectives CRPC = castration-resistant prostate cancer. Identify patient and tumor characteristics that can tailor CRPC treatment plans to individual patients Distinguish the safety and efficacy profiles of novel therapies for nonmetastatic and metastatic CRPC Apply strategies to manage adverse events associated with novel therapies for nonmetastatic and metastatic CRPC
  5. 5. Question 1 How many patients in your clinical practice have castration- resistant prostate cancer? a. Less than 10% b. 15-30% c. Over 50% d. I don’t see patients with prostate cancer
  6. 6. Question 2 PSA = prostate-specific antigen. A PSA doubling time <10 months is an indication of aggressive prostate cancer a. True b. False
  7. 7. Question 3 ADT = androgen deprivation therapy. Most men who start ADT will develop castration-resistant disease in approximately 23 months a. True b. False
  8. 8. Question 4 RADAR = Radiographic Assessments for Detection of Advanced Recurrence; m1 = metastatic. Crawford et al, 2018. The RADAR III group made which of the following recommendation(s) for serial imaging in men with M1 CRPC? a. When PSA ≥10 b. Every 6 to 9 months in absence of PSA rise c. When a patient develops new symptoms d. When there is a change in performance status e. (b), (c), and (d) f. All of the above
  9. 9. Question 5 CT = computed tomography. The following are treatment options for a man who has castration- resistant disease and rising PSA but no evidence of metastatic disease on CT scans and bone scan: a. Enzalutamide b. Abiraterone/prednisone c. Docetaxel/prednisone d. Bicalutamide e. Unsure
  10. 10. Incidence of Prostate Cancer Compared With Other Cancers in Men ACS, 2019. 0 20,000 40,000 60,000 80,000 100,000 120,000 140,000 160,000 180,000 200,000 Bladder Cancer Colon/Rectum Cancer Lung/Bronchus Cancer Prostate Cancer Estimated CRPC Prevalence Among Men in the United States in 2019: 186,050
  11. 11. Prostate Cancer Progression RT = radiation therapy. NCCN, 2019. Diagnosis Elevated PSA Biopsy Local therapy (surgery or RT) Undetectable PSA Rising PSA Biochemical recurrence
  12. 12. Progression to Castration-Resistant Prostate Cancer M0 = nonmetastatic; HSPC = hormone-sensitive prostate cancer. NCCN, 2019. Biochemical recurrence M0 HSPC M0 CRPC M1 CRPC M1 HSPC M1 CRPC
  13. 13. Definition of Castration-Resistant Prostate Cancer NCCN, 2019. Androgen deprivation Castrate levels of testosterone (<50 ng/dL) Rising PSA
  14. 14. Prostate Cancer Progression IV = intravenous; LHRH = luteinizing hormone-releasing hormone; LN = lymph node. NCCN, 2019. CRPC is classified as metastatic or nonmetastatic based on standard imaging (technetium bone scan and CT abdomen/pelvis with IV contrast) in clinical trials Imaging is critical to managing prostate cancer patients in order to correctly categorize and offer all appropriate treatment options • PSA decline • Testosterone <50 ng/dL LHRH • Castration resistance • No metastatic disease Rising PSA • Metastatic disease • Bone, LN, visceral metastases Rising PSA
  15. 15. Median Time to Progression on LHRH Therapy Ross et al, 2008; Scher et al, 2015. ADT Metastatic Cohort 15.9 months Nonmetastatic Cohort 33.2 months Retrospective analysis of 553 patients initiating LHRH therapy with metastatic (49%) and nonmetastatic (51%) disease
  16. 16. Imaging Is Critical in Prostate Cancer Management mCRPC = metastatic CRPC; nmCRPC = nonmetastatic CRPC; OMD = oligometastatic disease; ARPI = androgen receptor pathway inhibitor. Lecouvet et al, 2018.
  17. 17. Risk Stratification: PSA Doubling Time PSADT = PSA doubling time. Smith et al, 2013; Lecouvet et al, 2018. PSA doubling time: Can risk stratify men with biochemical recurrence Predicts at what PSA level imaging will likely show metastatic disease Associated with risk of bone metastasis or death, with PSADT ≤10 months considered an approximate inflection point in risk High risk: PSA ≥2 ng/mL, PSADT ≤10 months Low risk: PSA <2 ng/mL, PSADT >10 months
  18. 18. Case Study 1: John RP = radical prostatectomy; NED = no evidence of disease. 69-year-old man Diagnosed 5 years ago with Gleason 4+3 prostate cancer (elevated PSA  biopsy  RP); scans NED Diagnosed with biochemical recurrence 3 years ago; imaging negative for metastatic disease Starting LHRH therapy with PSA decline to 0.01 ng/mL Recent PSA readings: 1.5 ng/mL (6 months ago) 2.0 ng/mL (3 months ago) 3.0 ng/mL (today) Testosterone is <10 ng/dL CT scans and bone scan negative for metastatic disease
  19. 19. Case Study 1: John (cont.) AR = androgen receptor. How would you treat this patient? a. Continue on LHRH therapy b. Continue on LHRH therapy and add bicalutamide c. Continue on LHRH and add a second-generation AR inhibitor d. Unsure
  20. 20. NCCN: Systemic Therapy for Nonmetastatic CRPC NCCN = National Comprehensive Cancer Network; mo = month. NCCN, 2019.
  21. 21. Changing Treatment Landscape for M0 CRPC AAW = antiandrogen withdrawal. NCCN, 2019. Pre-2018 ADT (LHRH or orchiectomy) Bicalutamide AAW Enzalutamide Approved in July 2018 PROSPER Prior safety and efficacy in PREVAIL and AFFIRM Apalutamide Approved Feb 2018 SPARTAN Darolutamide Approved July 2019 ARAMIS
  22. 22. Second-Generation AR-Targeted Therapy MFS = metastasis-free survival; AEs = adverse events. El-Amm & Aragon-Ching, 2019; Fizazi et al, 2019. Apalutamide Enzalutamide Darolutamide Half-life 3-4 days 5.8 days 15.8 hours; 10 hours for metabolite Status FDA approved FDA approved FDA approved Metabolism Hepatic Hepatic Hepatic Dosage 240 mg orally once daily 160 mg orally once daily 600 mg orally twice daily Key phase 3 trial SPARTAN PROSPER ARAMIS N (patients) 1,207 1,401 1,502 MFS vs placebo (months) 40 vs 14.7 36.6 vs 13.6 40.4 vs 18.4 Serious AEs vs placebo (%) 25 vs 23 24 vs 18 25 vs 20
  23. 23. SPARTAN Trial: Apalutamide in Nonmetastatic CRPC CI = confidence interval. Smith et al, 2018.
  24. 24. SPARTAN Trial: Apalutamide Adverse Events Smith et al, 2018. Adverse Event Apalutamide (N=803) Placebo (N=398) Any grade Grade 3 or 4 Any grade Grade 3 or 4 Any adverse event 775 (96.5%) 362 (45.1%) 371 (93.2%) 136 (34.2%) Serious adverse event 199 (24.8%) – 92 (23.1%) – Adverse event leading to discontinuation of the trial regimen 85 (10.6%) – 28 (7.0%) – Adverse event associated with death 10 (1.2%) – 1 (0.3%) –
  25. 25. SPARTAN Trial: Apalutamide Adverse Events (cont.) aThis category includes adverse events that occurred up to 28 days after the last dose of the trial regimen was administered. bThese adverse events were considered by the investigators to be related to the trial regimen. cIndicates that mental impairment disorders included the following adverse events: disturbance in attention, memory impairment, cognitive disorder, and amnesia. Smith et al, 2018. Adverse Event Apalutamide (N=803) Placebo (N=398) Adverse events that occurred in ≥15% of patients in either groupa Any grade Grade 3 or 4 Any grade Grade 3 or 4 Fatigueb 244 (30.4%) 7 (0.9%) 84 (21.1%) 1 (0.3%) Hypertension 199 (24.8%) 115 (14.3%) 79 (19.8%) 47 (11.8%) Rashb 191 (23.8%) 42 (5.2%) 22 (5.5%) 1 (0.3%) Diarrhea 163 (20.3%) 8 (1.0%) 60 (15.1%) 2 (0.5%) Nausea 145 (18.1%) 0 63 (15.8%) 0 Weight loss 129 (16.1%) 9 (1.1%) 25 (6.3%) 1 (0.3%) Arthralgia 128 (15.9%) 0 30 (7.5%) 0 Fallsb 125 (15.6%) 14 (1.7%) 36 (9.0%) 3 (0.8 %) Other adverse events of interest Fractureb 94 (11.7%) 22 (2.7%) 26 (6.5%) 3 (0.8%) Dizziness 75 (9.3%) 5 (0.6%) 25 (6.3%) 0 Hypothyroidismb 65 (8.1%) 0 8 (2.0%) 0 Mental impairment disorderc 41 (5.1%) 0 12 (3.0%) 0 Seizureb 2 (0.2%) 0 0 0
  26. 26. PROSPER Trial: Enzalutamide in Nonmetastatic CRPC NR = not reached. Hussain et al, 2018.
  27. 27. PROSPER Trial: Enzalutamide Adverse Events Hussain et al, 2018. Event Enzalutamide Group (N=930) Placebo Group (N=465) All grades Grade ≥3 All grades Grade ≥3 Any adverse event 808 (87%) 292 (31%) 360 (77%) 109 (23%) Any serious adverse event 226 (24%) – 85 (18%) – Adverse event leading to discontinuation of trial regimen 87 (9%) – 28 (6%) – Adverse event leading to death 32 (3%) – 3 (1%) –
  28. 28. PROSPER Trial: Enzalutamide Adverse Events (cont.) Hussain et al, 2018. Event Enzalutamide Group (N=930) Placebo Group (N=465) Adverse events of special interest All grades Grade ≥3 All grades Grade ≥3 Hypertension 114 (12%) 43 (5%) 25 (5%) 11 (2%) Major adverse cardiovascular event 48 (5%) 34 (4%) 13 (3%) 8 (2%) Mental impairment disorders 48 (5%) 1 (<1%) 9 (2%) 0 Hepatic impairment 11 (1%) 5 (1%) 9 (2%) 2 (<1%) Neutropenia 9 (1%) 5 (1%) 1 (<1%) 1 (<1%) Convulsion 3 (<1%) 2 (<1%) 0 0 Posterior reversible encephalopathy syndrome 0 0 0 0
  29. 29. Nonmetastatic CRPC: Darolutamide Fizazi et al, 2019.
  30. 30. Darolutamide: Adverse Events of Interest Fizazi et al, 2019. Adverse Event Darolutamide (n=954) Placebo (n=554) Any Grade Grade 3/4 Any Grade Grade 3/4 Fatigue or asthenic conditions 15.8% 0.6% 11.4% 1.1% Bone fracture 4.2% 0.9% 3.6% 0.9% Falls, including accident 4.2% 0.8% 4.7% 0.7% Seizure, any event 0.2% 0 0.2% 0 Rash 2.9% 0.1% 0.9% 0 Weight decrease, any event 3.6% 0 2.2% 0 Dizziness, including vertigo 4.5% 0.2% 4.0% 0.2% Cognitive disorder 0.4% 0 0.2% 0 Memory impairment 0.5% 0 1.3% 0 Change in mental status 0 0 0.2% 0 Hypothyroidism 0.2% 0 0 0 Cerebral ischemia 1.4% 0.7% 1.4% 0.7% Coronary artery disorder 3.2% 1.7% 2.5% 0.4% Heart failure 1.9% 0.5% 0.9% 0
  31. 31. Metastatic Castration-Resistant Prostate Cancer
  32. 32. Genomic Testing All men with metastatic CRPC should undergo germline testing Tissue or blood testing sent to a lab for DNA sequencing Acquired alterations are responsible for cancer growth. Either cancer responds or doesn’t respond to therapy Next-generation sequencing should be used to test the prostate cancer for somatic mutations Identify possible targeted treatment options DNA = deoxyribonucleic acid. NCCN, 2019.
  33. 33. Skeletal-Related Events and M1 CRPC Zoledronic acid 4 mg IV every 4 weeks Denosumab 120 mg sq every 4 weeks Bone metastases are a common cause of morbidity in patients with prostate carcinoma. sq = subcutaneous. Fizazi et al, 2011; Saad et al, 2004.
  34. 34. NCCN: Systemic Therapy for Metastatic CRPC MSI-H = microsatellite instability-high; dMMR = deficient mismatch repair. NCCN, 2019.
  35. 35. Metastatic CRPC Treatment Options ECOG = Eastern Cooperative Oncology Group. NCCN, 2019. Second-generation AR inhibitors Abiraterone with prednisone Enzalutamide Chemotherapy Docetaxel and prednisone Cabazitaxel and prednisone Radium-223 Radiolabeled isotope Symptomatic metastatic prostate cancer to bone only Immunotherapy Sipuleucel-T Men with asymptomatic or minimally symptomatic M1 CRPC Slowly progressing disease No liver metastases ECOG 0-1 Not on opioids or steroids Pembrolizumab dMMR
  36. 36. Options for Metastatic Prostate Cancer NCCN, 2019. NO SOFT TISSUE DISEASE: Abiraterone acetate with prednisone Cabazitaxel Enzalutamide Radium-223 if symptomatic bone metastasis Pembrolizumab for MSI-H/dMMR Sipuleucel-T Clinical trial Best supportive care SOFT TISSUE DISEASE: Abiraterone with prednisone Cabazitaxel Pembrolizumab for MSI-H/dMMR Clinical trial Best supportive care
  37. 37. Case Study 2: Bill HTN = hypertension; ARB = angiotensin receptor blockers; dx = diagnosed; EBRT = external beam radiation; CXR = chest x-ray. 70-year-old man Past medical history HTN on ARB Hyperlipidemia on statin Family history Brother dx prostate cancer 67 Uncle dx prostate cancer 60 Father dx prostate cancer 58 Previous treatment ADT and EBRT Apalutamide M0 CRPC Imaging Bone scan with lesions noted in thoracolumbar spine CT scans of abdomen and pelvis: sclerotic lesions noted throughout thoracolumbar spine CXR ECOG 0 PSA 56 ng/mL Testosterone <10 ng/dL
  38. 38. Case Study 2: Bill (cont.) In your clinical practice, which of the following treatment options would you choose for Bill for his castration-resistant metastatic prostate cancer? a. Sipuleucel-T b. Docetaxel/prednisone c. Enzalutamide d. Abiraterone/prednisone e. Radium-223 f. Cabazitaxel/prednisone
  39. 39. Sipuleucel-T in Metastatic CRPC Kantoff et al, 2010. Autologous activated cellular immunotherapy Improved median overall survival compared with placebo 25.8 vs 21.7 months Adverse events more frequent in the sipuleucel-T group: Chills Fever Headache
  40. 40. Case Study 2: Bill (cont.) sip-T = sipuleucel-T. Imaging Bone scan remains stable, with lesions noted in thoracolumbar spine CT scans of abdomen and pelvis: sclerotic lesions noted throughout thoracolumbar spine 0 10 20 30 40 50 60 70 80 90 Feb-18 Apr-18 Jun-18 Aug-18 Oct-18 Dec-18 Feb-19 PSA Elects to proceed with sip-T Completes treatment ECOG 1 (fatigue) PSA continues to rise Sipuleucel-T
  41. 41. Case Study 2: Bill (cont.) Counseled to undergo next-generation sequencing Consider referral to genetic counselor MLH1, MSH2, MSH6, PMS2, BRCA1/2, ATM, PALB2, CHEK2 Discussed options for treatment Abiraterone/prednisone Enzalutamide Docetaxel/prednisone Radium-223
  42. 42. Interference With Androgenic Stimulation: Abiraterone PO = oral administration; QD = once daily; BID = twice daily; LFTs = liver function tests. Ryan et al, 2015. Abiraterone/prednisone Blocks CYP17 gene Blocks synthesis of androgens in the tumor, testes, and adrenal gland Decreases cortisol production Dosing: 1,000 mg PO QD on empty stomach Prednisone 5 mg BID with food Side effects Fatigue Electrolyte imbalances Hypertension Fluid retention Joint aches and pains Diarrhea Elevated LFTs
  43. 43. Interference With Androgenic Stimulation: Enzalutamide Xtandi® prescribing information, 2018. Acts at multiple sites in androgen signaling pathway Blocks binding of androgen to AR 160 mg PO QD With or without food No steroid requirement Side effects Fatigue/asthenia Increased risk of falls/fractures Dizziness/headaches/seizures Hypertension Nausea/constipation Cognitive and attention disorders
  44. 44. Chemotherapy: Docetaxel NCCN, 2019; Taxotere prescribing information, 2013. Docetaxel 75 mg/m2 every 21 days up to 10 cycles; prednisone 5 mg PO BID Consider in men who are symptomatic Short response to primary ADT Prolongs overall survival Side effects Myelosuppression Nausea/vomiting Diarrhea/constipation Peripheral neuropathies Fatigue Elevated LFTs Partial hair loss
  45. 45. Nursing Management NCCN, 2019; Taxotere prescribing information, 2013. Abiraterone/prednisone and enzalutamide Oral medications dosed at home Interactions with food and meds Electrolyte and LFTs Blood pressure monitoring Side effect monitoring Docetaxel and prednisone IV chemotherapy Antiemetics Premedication for infusion reaction Side effect monitoring and management
  46. 46. Radium-223 Wilson & Parker, 2016; Xofigo® prescribing information, 2018. One-minute monthly injection with a radioisotope which travels to metastatic sites in bone Delivers targeted radiation to (multiple) sites of bone breakdown Side effects: nausea, vomiting, diarrhea, low blood counts, and fatigue
  47. 47. Radium-223 Versus Best Supportive Care Parker et al, 2013.
  48. 48. Radium-223: Warnings and Precautions Parker et al, 2013; Xofigo® prescribing information, 2018. Bone marrow suppression Measure blood counts prior to treatment initiation and before every dose of radium-223 Discontinue if hematologic values do not recover within 6 to 8 weeks after treatment Closely monitor patients with compromised bone marrow reserve Discontinue in patients who experience life-threatening complications despite supportive care measures Ensure that men are on bone-strengthening agents Not recommended in combination with abiraterone acetate plus prednisone or prednisolone Increased fractures and mortality
  49. 49. Case Study 3: Mark Hx = history; CAD = coronary artery disease; d/t = due to. 75-year-old man with a hx of HTN, hyperlipidemia, and CAD presenting with M1 CRPC Treatment history following RP 10 years ago: LHRH. Added enzalutamide for M0 CRPC. He was treated for approximately 33 months Progressed to M1 CRPC with multiple bone lesions, retroperitoneal adenopathy, and bone pain 2 years ago Docetaxel and prednisone x 10 cycles. Stopped d/t hematologic toxicity. Stable disease Bisphosphonates added Progression of disease with new bone lesions. No current adenopathy or soft tissue disease. ECOG 1
  50. 50. Case Study 3: Mark (cont.) AST/ALT = aspartate aminotransferase/alanine aminotransferase; bili = bilirubin; WNL = within normal limits; Alk phos = alkaline phosphatase. Treated with radium-223 x 6 cycles Follow-up imaging with stable bone lesions CT scans with enlarging LN and 2 approximately 1-cm lesions in the liver concerning for metastases AST/ALT, total bili are WNL. Alk phos 455 Next-generation sequencing reveals BRCA1 mutation and dMMR Presenting for discussion of treatment options
  51. 51. NCCN: Systemic Therapy for Metastatic CRPC NCCN, 2019.
  52. 52. Chemotherapy: Cabazitaxel NCCN, 2019. Dosage: 20 mg/m2 or 25 mg/m2 For patients who have progressed despite prior docetaxel Consider prednisone for healthy men who prefer more aggressive treatment Side effects (higher with 25-mg dose) Febrile neutropenia Diarrhea Fatigue Nausea/vomiting Anemia Thrombocytopenia Sepsis Renal failure
  53. 53. FIRSTANA: Cabazitaxel vs Docetaxel C20 = cabazitaxel 20 mg/m2; C25 = cabazitaxel 25 mg/m2; D75 = docetaxel 75 mg/m2. Oudard et al, 2017.
  54. 54. FIRSTANA: Notable Safety Differences Oudard et al, 2017. Adverse Event C20 C25 D75 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade ≥3 Febrile neutropenia 2.4% 2.4% 12.0% 12.0% 8.3% 8.3% Diarrhea 32.5% 3.5% 49.9% 5.6% 37.0% 2.3% Hematuria 20.3% 3.5% 25.1% 3.6% 3.6% 0.3% Peripheral neuropathy 11.7% 0.3% 12.3% 0% 25.1% 2.1% Peripheral edema 9.8% 0% 7.7% 0.3% 20.4% 1.6% Alopecia 8.9% 0% 13.0% 0% 39.0% 0% Nail disorders 0.3% 0% 0.8% 0% 9.0% 0.3%
  55. 55. Pembrolizumab in M1 CRPC: KEYNOTE-199 PD-L1 = programmed death-ligand 1; mets = metastasis; RECIST = Response Evaluation Criteria in Solid Tumors. de Bono et al, 2018.
  56. 56. DNA Repair Deficiency Mutations Can Be Present and Predict Response to PARP Inhibitors PARP = poly(ADP-ribose) polymerase. Mateo et al, 2015.
  57. 57. Patient-Centered Prostate Cancer Treatment QOL = quality of life. Science- and evidence-driven More focus on QOL issues for men and their families Continuously improving supportive care interventions Hope for a cure
  58. 58. Future Considerations: Clinical Research Huehls et al, 2015; Silvestri et al, 2019. Immunotherapy in combination or with targeted agents More data on watchful waiting Refine genomic testing with more targeted treatments PARP inhibitors
  59. 59. Key Takeaways PSADT can risk stratify patients with nonmetastatic CRPC The androgen receptor remains the most important driver in the continuum of CRPC Prostate cancer therapy is a marathon Make sure we get the most mileage out of each treatment More than one right sequencing strategy Look for trial opportunities EARLY Genomics are increasingly important for individualizing therapy Sequencing of therapies is an active area of interest
  60. 60. References American Cancer Society (2019). Cancer facts & figures 2019. Available at: Crawford ED, Koo PJ, Shore N, et al (2018). A clinician’s guide to next generation imaging in patients with advanced prostate cancer (RADAR III). J Urol, 201(4):682-692. DOI:10.1016/j.juro.2018.05.164 de Bono JS, Goh JCH, Ojamaa K, et al (2018). KEYNOTE-199: pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol, 36(suppl_15):5007. DOI:10.1200/JCO.2018.36.15_suppl.5007 El-Amm J & Aragon-Ching JB (2019). The current landscape of treatment in non-metastatic castration-resistant prostate cancer. Clin Med Insights Oncol, 13:1179554919833927. DOI:10.1177/1179554919833927. ErleadaTM (apalutamide) prescribing information (2019). Janssen Biotech, Inc. Available at: pi.pdf Fizazi K, Carducci M, Smith M, et al (2011). Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomized, double-blind study. The Lancet, 9768(377):813-822. DOI:10.1016/S0140-6736(10)62344-6 Fizazi K, Shore N, Tammela TL, et al (2019). Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med, 380(13):1235-1246. DOI:10.1056/NEJMoa1815671 Huehls AM, Coupet TA & Sentman CL (2015). Bispecific T-cell engagers for cancer immunotherapy. Immunol Cell Biol, 93(3):290-296. DOI:10.1038/icb.2014.93 Hussain M, Fizazi K, Saad F, et al (2018). Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med, 378:2465. DOI:10.1056/NEJMoa1800536 Kantoff PW, Higano CS, Shore ND, et al (2010). Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med, 363:411-422. DOI:10.1056/NEJMoa1001294 Lecouvet F, Oprea-Lager D, Liu Y, et al (2018). Use of modern imaging methods to facilitate trials of metastasis-directed therapy for oligometastatic disease in prostate cancer: a consensus recommendation from the EORTC Imaging Group. Lancet Oncol, 10(19):e534-e545. DOI:10.1016/S1470-2045(18)30571-0 Mateo J, Carreira S, Sandhu S, et al (2015). DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med, 373:1697-1708. DOI:10.1056/NEJMoa1506859 National Comprehensive Cancer Network (2019). Clinical Practice Guidelines in Oncology: prostate cancer. Version 1.2019. Available at: National Comprehensive Cancer Network (2018). NCCN Guidelines for Patients: prostate cancer. Available at: Oudard S, Fizazi K, Sengelov L, et al (2017). Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: a randomized phase III trial— FIRSTANA. J Clin Oncol, 35(28):3189-3197. DOI:10.1200/JCO.2016.72.1068 Parker C, Nilsson S, Heinrich D, et al (2013). Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med, 369:213-223. DOI:10.1056/NEJMoa1213755 Ross RW, Xie X, Regan MM, et al (2008). Efficacy of androgen deprivation therapy (ADT) in patients with advanced prostate cancer: association between Gleason score, prostate-specific antigen level, and prior ADT exposure with duration of ADT effect. Cancer, 112(6):1247-1253. DOI:10.1002/cncr.23304 Ryan CJ, Smith MR, Fizazi K, et al (2015). Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol, 16(2):152-60. DOI:10.1016/S1470-2045(14)71205-7
  61. 61. References (cont.) Saad F, Gleason DM, Murray R, et al (2004). Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst, 96(11):879-882. Silvestri I, Tortorella E, Giantulli S, et al (2019). Immunotherapy in prostate cancer: recent advances and future directions. EMJ Urol, 7(1):51-61. Smith M, Saad F, Chowdhury S, et al (2018). Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med, 378:1408. DOI:10.1056/NEJMoa1715546 Smith M, Saad F, Oudard S, et al (2013). Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol, 31(30):3800-3806. DOI:10.1200/JCO.2012.44.6716 Taxotere (docetaxel) prescribing information (2013). Sanofi-Aventis. Available at: Wilson JM & Parker C (2016). The safety and efficacy of radium-223 dichloride for the treatment of advanced prostate cancer. Expert Rev Anticancer Ther, 16(9):911-918. DOI:10.1080/14737140.2016.1222273 Xofigo® (radium-223) prescribing information (2018). Bayer. Available at: Xtandi® (enzalutamide) prescribing information (2018). Astellas Pharma US, Inc., and Pfizer Inc. Available at: