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Defining Personalized Care Plans in Metastatic Castration-Resistant Prostate Cancer

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Defining Personalized Care Plans in Metastatic Castration-Resistant Prostate Cancer

  1. 1. Defining Personalized Care Plans in Metastatic Castration-Resistant Prostate Cancer Tanya B. Dorff, MD Associate Professor of Clinical Medicine USC Keck School of Medicine USC Norris Comprehensive Cancer Center
  2. 2. ACCREDITATION This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and i3 Health. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians. The Postgraduate Institute for Medicine designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. The Postgraduate Institute for Medicine is accredited with distinction as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. This educational activity for 1.0 contact hours is provided by Postgraduate Institute for Medicine. Designated for 0.8 contact hours of pharmacotherapy credit for Advance Practice Registered Nurses. INSTRUCTIONS TO RECEIVE CREDIT In order to receive credit for this activity, participants must: 1. Participate in the live webinar 2. Complete and submit the posttest and activity evaluation via the link provided after the webinar 3. Download or print their Certificate of Credit 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 Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. COMMERCIAL SUPPORT This activity is supported by independent educational grants from Bayer HealthCare Pharmaceuticals Inc. and Genzyme.
  3. 3. Disclosures ▶ Dr. Dorff discloses the following commercial relationships: ◼ Consultant: Bayer, Dendreon, Eisai, EMD Serono, Exelixis, Janssen ◼ Speakers’ Bureau: Exelixis ▶ The PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi Smelker-Mitchek, MBA, MSN, RN, and Jan Schultz, MSN, RN, CHCP have nothing to disclose ▶ The i3 Health planners and managers have nothing to disclose
  4. 4. Learning Objectives ▶ Evaluate recent study findings on combination and sequential treatment strategies for patients with metastatic CRPC ▶ Determine which predictive/prognostic biomarker tests are ready for application in metastatic CRPC practice ▶ Utilize strategies for evaluating treatment response, incorporating imaging studies, prostate-specific antigen levels, and clinical findings CRPC = castration-resistant prostate cancer.
  5. 5. Mr. JW: 57-Year-Old Man PSA = prostate-specific antigen; LE = lower extremity. ◼ PSA 125 ng/mL ◼ Gleason 5+5 ◼ Osseous metastases ◼ L3-L4 epidural extension of tumor with LE weakness ◼ Received degarelix April 2013 + surgical decompression and radiation ◼ PSA dropped to 0.06 ng/mL within 3 mo ◼ Developed early castration resistance at 6 months with PSA rising to 0.48 ng/mL and then 1.1 ng/mL ◼ Asymptomatic Diagnosis Castration ResistanceInitial Therapy
  6. 6. Mr. JW: Castration Resistance
  7. 7. Mr. JW: Next Step? Sipuleucel-T Abiraterone Enzalutamide DocetaxelCabazitaxel Radium-223 Combination Therapy Treatment Options
  8. 8. New “Life Extending Therapies” for Metastatic CRPC ▶ Abiraterone ◼ COU301: Median OS 14.8 vs 10.9 mo for placebo (post-TAX) ◼ COU302: PFS 16.5 vs 8.3 mo for placebo (pre-TAX) ▶ Cabazitaxel ◼ Median OS 15.1 vs 12.7 mo mitoxantrone (post-TAX) ▶ Enzalutamide ◼ AFFIRM: Median OS 18.4 mo vs 13.6 mo for placebo (post- TAX) ◼ PREVAIL: Median OS 32.4 mo vs 30.2 mo pre-TAX (17 mo delay in chemo) OS = overall survival; TAX = taxane therapy; PFS = progression-free survival. de Bono et al, 2011; Rathkopf et al, 2014; de Bono et al, 2010; Scher et al, 2012; Beer et al, 2014.
  9. 9. New “Life Extending Therapies” for Metastatic CRPC (cont.) ▶ Radium-223 ◼ ALSYMPCA: Median OS 14.9 vs 11.3 mo for placebo ▶ Sipuleucel-T ◼ IMPACT: Median OS 23.2 vs 18.9 mo for placebo Parker et al, 2013; Higano et al, 2009.
  10. 10. Metastatic CRPC: Defining a “Meaningful” Improvement in OS Schellhammer et al, 2013.
  11. 11. ▶ Autologous activated cellular immunotherapy Sipuleucel-T Immunotherapy Kantoff et al, 2010. Sipuleucel-T
  12. 12. Sipuleucel-T Immunotherapy (cont.) Higano et al, 2009.
  13. 13. Abiraterone (CYP17 Inhibitor) Boron & Boulpaep, 2003.
  14. 14. OS HR=0.79 for AA+P Pre-Docetaxel (P=0.019) COU302 Trial: Abiraterone AA + P = abiraterone acetate + prednisone. Rathkopf et al, 2014.
  15. 15. Abiraterone: Adverse Events de Bono et al, 2011.
  16. 16. Enzalutamide: Androgen Receptor Antagonist Image courtesy of Tanya B. Dorff, MD.
  17. 17. PREVAIL Trial: Enzalutamide vs Placebo Beer et al, 2014.
  18. 18. Enzalutamide: Adverse Events Beer et al, 2014.
  19. 19. Petrylak et al, 2004. SWOG 9916: Docetaxel in Metastatic CRPC
  20. 20. TAX 327: Docetaxel in Metastatic CRPC Tannock et al, 2004.
  21. 21. Docetaxel: Adverse Events Tannock et al, 2004.
  22. 22. TREATMENT 6 injections at 4-week intervals Radium-223 (50 kBq/kg) + Best BSC Placebo (saline) + BSC R A N D O M I Z E D 2:1 N=921 PATIENTS  Confirmed symptomatic CRPC  ≥2 bone metastases  No known visceral metastases  Post- docetaxel or unfit for docetaxel  Total ALP: <220 U/L vs ≥220 U/L  Bisphosphonate use: Yes vs No  Prior docetaxel: Yes vs No STRATIFICATION ALSYMPCA Phase III: Radium-223 vs BSC BSC = best standard of care; ALP = alkaline phosphatase; U/L = units per liter. Parker et al, 2013.
  23. 23. ALSYMPCA: Overall Survival Parker et al, 2013.
  24. 24. ALSYMPCA: Time to First Symptomatic Skeletal Event Parker et al, 2016.
  25. 25. ALSYMPCA: Adverse Events Parker et al, 2013.
  26. 26. Mr. JW (cont.) How would you treat this patient? a. Abiraterone b. Docetaxel c. Enzalutamide d. Sipuleucel-T e. Other (including combinations)
  27. 27. Considerations for This Patient ▶ Abiraterone ◼ Impaired insulin sensitivity ▶ Enzalutamide ◼ History of seizures or falls ◼ Visceral disease ▶ Docetaxel ◼ Neuropathy (could substitute cabazitaxel) ◼ Risk of infection ▶ Radium-223 ◼ Symptomatic bone metastases without soft tissue ▶ Sipuleucel-T ◼ Venous access (pheresis catheter increases risk of morbidity) Oudard et al, 2017; NCCN, 2017. Add bone support with zoledronic acid or denosumab!
  28. 28. Novel Combination Strategies Trial Agents Accrual (N) Status CTSU A031201 Enza Enza + Abi N=1,311 Completed 8/31/16 Bayer 16544 Rad223 Rad223 + Abi Rad223 + Enza N=68 Resulted; ORR favors combination PEACE III Enza Enza + Rad223 N=560 Still recruiting ERA 223 Abi Abi + Rad223 N=806 Completed NCT02218606 Abi Abi + Cabazitaxel N=55 Recruiting ▶ No level 1 data YET to support combinations ▶ Single sequential remains standard outside of clinical trial Clinicaltrials.gov, 2017a; Clinicaltrials.gov, 2017b; Clinicaltrials.gov, 2017c; Clinicaltrials.gov, 2017d; Clinicaltrials.gov, 2017e.
  29. 29. Novel Combination Strategies (cont.) DRD = DNA repair defects. Clinicaltrials.gov, 2017f; Hussain et al, 2016; Clinicaltrials.gov, 2017g; Clinicaltrials.gov, 2017h; Clinicaltrials.gov, 2017i; Reichert et al, 2017. Trial Agents Accrual (N) Target Status CO39303 Abi Abi + ipatasertib N=850 AKT Accruing NCT01576172 Abi Abi + veliparib N=148 PARP Reported IMbassador250 Enza Enza + atezolizumab N=730 PD-L1 Accruing NCT02257736 Abi Abi + apalutamide N=983 AR Completed NCT03093428 Rad223 Rad223 + pembrolizumab N=45 PD-L1 Accruing NCT03012321 Abi Olaparib Abi + olaparib N=60 PARP Accruing (restricted to DRD)
  30. 30. Mr. JW (cont.) ◼ Enrolled on clinical trial (abiraterone with prednisone ± dasatinib) ◼ Randomly assigned to abiraterone ◼ Started treatment in with baseline PSA of 5.24 ng/mL ◼ PSA decreased to 0.14 ng/mL but then began to rise slowly ◼ PSA 2.2 ng/mL but feeling well and no radiographic change May 2014 August 2015October 2014
  31. 31. Mr. JW (cont.) Would you switch therapy or add therapy?
  32. 32. Monitoring Treatment Response ▶ PSA change alone should not be used as a trigger to switch therapy if patients feel well and imaging shows no change ▶ Imaging to evaluate response recommended every 8-9 weeks during first 24 weeks, then every 12 weeks Scher et al, 2016.
  33. 33. Monitoring Treatment Response (cont.) ▶ Due to “flare” phenomenon (new bone lesions despite improvement in disease) new lesions on a bone scan at first assessment do not constitute disease progression ◼ Requires confirmation with additional new lesions on the following scan ▶ When new lesions detected after 12 weeks, confirmation of progression requires persistence of the new lesions but not additional new lesions Scher et al, 2016.
  34. 34. Mr. JW (cont.) ▶ December 2015: PSA reaches 5 ng/mL and patient reports more pain in both hips ▶ Referred for palliative radiation ▶ Patient asks about the next treatment plan
  35. 35. Mr. JW: 55-Year-Old Man (cont.) How would you treat this patient now? a. Cabazitaxel b. Docetaxel c. Enzalutamide d. Radium-223 e. Other (including combinations) Do you continue abiraterone “adding” an agent above or do you switch?
  36. 36. Decreased Efficacy of AR Targeted Therapy in Sequence Loriot et al, 2013. Abiraterone response after prior treatment with enzalutamide
  37. 37. Enzalutamide vs Docetaxel in Men With CRPC Progressing After Abiraterone Decreased Efficacy of AR Targeted Therapy in Sequence Suzman et al, 2014.
  38. 38. GR = glucocorticoid receptor; SCC = small cell carcinoma; NEPC = neuroendocrine prostate cancer. Watson et al, 2015. Androgen Receptor Splice Variant-7
  39. 39. Can ARV7 Help Select Treatment? ARV7 = androgen receptor splice variant-7. Antonarakis et al, 2015. ARV7 Not Associated With Lack of Response to Docetaxel
  40. 40. ARV7 Predicts Less Response to Enzalutamide Antonarakis et al, 2014. Can ARV7 Help Select Treatment? (cont.)
  41. 41. Antonarakis et al, 2014. Can ARV7 Help Select Treatment? (cont.) ARV7 Predicts Less Response to Abiraterone
  42. 42. ARV7: Not Yet Ready for Use in Treatment Selection TBD = to be determined; CTC = circulating tumor cell; ddPCR = droplet digital polymerase chain reaction. Grande et al, 2016; Scher et al, 2017; Clinicaltrials.gov, 2017j. ▶ SOGUG PREMIERE trial of enzalutamide – PSA responses seen in ARV7+ patients ▶ ARMOR study (in ARV7 selected population) closed for futility ◼ 953 screened, 73 enrolled ◼ PSA response 13% galeterone, 42% enzalutamide ▶ ARV7 more complicated than originally thought ◼ Amount? Timing (transient)? ◼ Localization of AR ▶ Optimal assay TBD ◼ CTC based ◼ Plasma ddPCR for AR amplification/mutation
  43. 43. ARV7: Not Yet Ready for Use in Treatment Selection (cont.) Conteduca et al, 2017.
  44. 44. Are CTC Counts Useful in Managing Patients With Metastatic CRPC? de Bono et al, 2008.
  45. 45. Single Sequential Remains the Standard Paradigm Attard et al, 2017.
  46. 46. Single Sequential Remains the Standard Paradigm (cont.) Attard et al, 2017.
  47. 47. Mr. JW (cont.) ▶ Abiraterone was discontinued ▶ Received docetaxel x 8 cycles with stable disease ▶ Upon PSA progression received enzalutamide ◼ A few months later radium-223 was added due to emerging bone pain ▶ Now PSA is rising again. Patient has good performance status and organ function
  48. 48. Non-AR Targeted Agents Under Investigation Agent(s) Target Select Population Phase of Trial Niraparib, Olaparib, Rucaparib, Talazoparib PARP DNA repair deficient or non-selected (in combinations) II and III Cabozantinib VEGF, c-Met Unselected Ib/II (with ipi/nivo) Palbociclib CDK4/6 Unselected II Pembrolizumab PD-1 Progressing on enzalutamide II Durvalumab ± Tremelimumab PD-L1 CTLA4 Unselected II Lu177-j591 PSMA Unselected II MLN 8237 (alisertib) Aurora Kinase Small cell/neuroendocrine II GSK525762 BET Progression on enza/abi Ib LY2606368 Chk1/2 BRCA mutated I Mateo et al, 2015; Ryan et al, 2017; Reinstein et al, 2017; Clinicaltrials.gov, 2017k; Graff et al, 2016a; Silvestri et al, 2016; Tagawa et al, 2013; Graff et al, 2016b; Clinicaitrials.gov, 2017l; Clinicaltrials.gov, 2017m. Clinicaltrials.gov, 2017n.
  49. 49. DNA Repair Deficiency Predicts Response to PARP Inhibitors PARP = poly ADP ribose polymerase. de Lartigue, 2013.
  50. 50. DNA Repair Deficiency Predicts Response to PARP Inhibitors (cont.) Mateo et al, 2015.
  51. 51. DNA Repair Deficiency Is Common in Metastatic CRPC and Prognostic Hussain et al, 2017; Pritchard et al, 2016. Arm A: Abiraterone (n=31) Arm B: Abiraterone + Veliparib (n=44)
  52. 52. Key Takeaways ▶ Single sequential treatment remains only strategy with level 1 evidence ◼ Combination trials underway/completed ▶ Imaging is important for monitoring treatment response ◼ PSA rise alone usually not enough to indicate treatment change ▶ No current biomarker to select patients for treatment ◼ DNA repair deficiency may select for PARP inhibitor, common in metastatic prostate cancer. Consider screening ◼ ARV7 assay needs validation before implementation
  53. 53. Key Takeaways (cont.) ▶ Future treatment may include immune checkpoint inhibitors and/or PARP inhibitors Consider referring for clinical trials early given that combination trials with standard agents are very common.
  54. 54. Audience Q&As Use the Questions section of your Control Panel to submit questions to the faculty.
  55. 55. To receive CME/CE credit visit: www.i3health.com/CRPC
  56. 56. References Antonarakis ES, Lu C, Chen Y, et al (2015). AR splice variant 7 (AR-V7) and response to taxanes in men with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol (2015 Genitourinary Cancers Symposium Abstracts), 33(suppl 7). Abstract 138. Antonarakis ES, Lu C, Wang H, et al (2014). AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med, 371(11):1028-1038. DOI:10.1056/nejmoa1315815 Attard G, Borre M, Gurney H, et al (2017). A phase IV, randomized, double-blind, placebo (PBO)-controlled study of continued enzalutamide (ENZA) post prostate-specific antigen (PSA) progression in men with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol (ASCO Annual Meeting Abstracts), 35(uppl 15). Abstract 5004. Beer TM, Armstrong AJ, Rathkopf DE, et al (2014). Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med, 371(5):424-433. DOI:10.1056/nejmoa1405095 Boron WF & Boulpaep EL (2003). In: Medical Physiology: A Cellular and Molecular Approach, Elsevier/Saunders. Clinicaltrials.gov (2017a). Enzalutamide with or without abiraterone and prednisone in treating patients with castration-resistant metastatic prostate cancer. NLM identifier: NCT01949337 Clinicaltrials.gov (2017b). A randomized phase IIa efficacy and safety study of radium-223 dichloride with abiraterone acetate or enzalutamide in metastatic castration-resistant prostate cancer (CRPC). NLM identifier: NCT02034552 Clinicaltrials.gov (2017c). Phase III radium-223 mCRPC-PEACE III. NLM idenfifier: NCT02194842 Clinicaltrials.gov (2017d). Radium-223 dichloride and abiraterone acetate compared to placebo and abiraterone acetate for men with cancer of the prostate when medical or surgical castration does not work and when the cancer has spread to the bone, has not been treated with chemotherapy and is causing no or only mild symptoms (ERA 223). NLM identifier: NCT02043678 Clinicaltrials.gov (2017e). Multicenter trial of abiraterone acetate with or without cabazitaxel in treatment of metastatic castration resistant prostate cancer. NLM identifier: NCT02218606 Clinicaltrials.gov (2017f). Ipatasertib plus abiraterone plus prednisone/prednisolone, relative to placebo plus abiraterone plus prednisone/prednisolone in adult male patients with metastatic castrate-resistant prostate cancer (IPATential150). NLM identifier: NCT03072238 Clinicaltrials.gov (2017g). A study of atezolizumab (anti-PD-L1 antibody) in combination with enzalutamide in participants with metastatic castration-resistant prostate cancer (mCRPC) after failure of an androgen synthesis inhibitor and failure of, ineligibility for, or refusal of a taxane regimen (IMbassador250). NLM identifier: NCT03016312 Clinicaltrials.gov (2017h). An efficacy and safety study of apalutamide (JNJ-56021927) in combination with abiraterone acetate and prednisone versus abiraterone acetate and prednisone in participants with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). NLM identifier: NCT02257736
  57. 57. References Clinicaltrials.gov (2017i). Study evaluating the addition of pembrolizumab to radium-223 in mCRPC. NLM idenfier: NCT03093428 Clinicaltrials.gov (2017j). A study of galeterone compared to enzalutamide in men expression androgen receptor splice varian—7 mRNA (AR- V7) metastatic CRPC (ARMOR3-SV). NLM identifier: NCT002438007 Clinicaltrials.gov (2017k). Cabozantinib-s-malate and nivolumab with or without ipilimumab in treating patients with metastatic genitourinary tumors. NLM identifier: NCT02496208 Clinicaltrials.gov (2017l). Palbociclib in patients with metastatic castration-resistant prostate cancer. NLM identifier: NCT02905318 Clinicaltrials.gov (2017m). Dose escalation and dose expansion study of GSK525762 in combination with androgen deprivation therapy and other agents in subjects with castrate-resistant prostate cancer. NLM identifier: NCT03150056 Clinicaltrials.gov (2017n). A phase II single arm pilot study of the ChL1/2 inhibitor (LY2606368) in BRCA1/2 mutation associated breast or ovarian cancer, triple negative breast cancer, high grade serous ovarian cancer, and metastatic castrate-resistant prostate cancer. NLM identifier: NCT02203513 Conteduca V, Wetterskog D, Sharabiani MTA, et al (2017). Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study. Ann Onc, 28:1508- 1516. DOI:10.1093/annonc/mdx155 de Bono JS, Logothetis CJ, Molina A, et al (2011). Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med, 364(21):1995-2005. DOI:10.1056/nejmoa1014618 de Bono JS, Oudard S, Ozguroglu M, et al (2010). Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet, 376(9747):1147-1154. DOI:10.1016/s0140- 6736(10)61389-x de Bono JS, Scher HI, Montgomery RB, et al (2008). Circulating tumor cells predict survival benefit from treatment in metastatic castration- resistant prostate cancer. Clin Cancer Res, 14(19):6302-6309. DOI:10.1158/1078-0432.CCR-08-0872 de Lartigue J (2013). New life for PARP inhibitors: emerging agents leave mark at ASCO. OncLive. Available at: http://www.onclive.com/publications/oncology-live/2013/august-2013/new-life-for-parp-inhibitors-emerging-agents-leave-mark-at- asco?p=1 Graff JN, Alumkal JJ, Drake CG, et al (2016a). Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget, 7(33):52810-52817. DOI:10.18632/oncotarget.10547 Graff JN, Higano CS, Hahn NM, et al (2016b). Open-label, multicenter, phase 1 study of alisertib (MLN8237), an aurora A kinase inhibitor, with docetaxel in patients with solid tumors. Cancer, 122(16):2524-2533. DOI:10.1002/cncr.30073
  58. 58. References Grande E, Fernandez Perez MP, Font A, et al (2016). Early responses to enzalutamide in AR-V7 positive first line metastatic castration-resistant prostate cancer (mCRPC). A prospective SOGUG clinical trial: the PREMIERE study. Ann Onc (ESMO 2016 Annual Meeting Abstracts), 27(suppl 6). Abstract 726PD. Higano CS, Schellhammer PF, Small EJ, et al (2009). Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer, 115(16):3670-3679. DOI:10.1002/cncr.24429 Hussain M, Daignault S, Twardowski P, et al (2017). Abiraterone + prednisone (Abi) +/- veliparib (Vel) for patients (pts) with metastatic castration-resistant prostate cancer (CRPC): NCI 9012 updated clinical and genomics data. J Clin Oncol (ASCO Annual Meeting Abstracts), 35. Abstract 5001. Hussain M, Daignault S, Twardowski P, et al (2016). Co-targeting androgen receptor (AR) and DNA repair: a randomized ETS gene fusion- stratified trial of abiraterone + prednisone (Abi) +/- the PARP1 inhibitor veliparib for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol (ASCO Annual Meeting Abstracts), 34. Abstract 5010. Kantoff PW, Higano CS, Shore ND, et al (2010). Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med, 363(5):411-422. DOI:10.1056/nejmoa1001294 Loriot Y, Bianchini D, Ileana E, et al (2013). Antitumor activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV-3100). Ann Oncol, 24(7):1807-1812. DOI:10.1093/annonc/ndt136 Mateo J, Carreira S, Sandhu S, et al (2015). DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med, 373(18):1697-1708. DOI:10.1056/nejmoa1506859 National Comprehensive Cancer Network (2017). NCCN Clinical Practice Guidelines in Oncology: prostate cancer. Version 2.2017. Available at: http://www.nccn.org Oudard S, Fizazi K, Sengeløv 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. [Epub ahead of print] 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(3):213- 223. DOI:10.1056/nejmoa1213755 Petrylak DP, Tangen CM, Hussain MHA, et al (2004). Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med, 351(15):1513-1520. DOI:10.1056/nejmoa041318 Pritchard CC, Mateo J, Walsh MF, et al (2016). Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med, 374(5):443-453. DOI:10.1056/nejmoa1603144
  59. 59. References Rathkopf DE, Smith MR, de Bono JS, et al (2014). Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Eur Urol, 66(5):815-825. DOI:10.1016/j.eururo.2014.02.056 Reichert Z, Carneiro BA, Daighnault-Newton S, et al (2017). A randomized phase II trial of abiraterone, olaparib, or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair defects. J Clin Oncol, 35(15_suppl). DOI:10.1200/JCO.2017.35.15_suppl.TPS5086 Schellhammer PF, Chodak G, Whitemore JB, et al (2013). Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the immunotherapy for prostate adenocarcinoma treatment (IMPACT) trial. Urology, 81(6):1297-1302. DOI:10.1016/j.urology.2013.01.061 Scher HI, Fizazi K, Saad F, et al (2012). Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med, 367(13):1187-1197. DOI:10.1056/nejmoa1207506 Scher HI, Graf RP, Schreiber NA et al (2017). Nuclear-specific AR-V7 protein localization is necessary to guide treatment selection in metastatic castration-resistant prostate cancer. Eur Urol, 71(6):874-882. DOI:10.1016/j.eururo.2016.11.024 Scher HI, Morris MJ, Stadler WM, et al (2016). Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3. J Clin Oncol, 34(12):1402-1418. DOI:10.1200/jco.2015.64.2702 Silvestri I, Cattarino S, Giantulli S, et al (2016). A perspective of immunotherapy for prostate cancer. Cancers (Basel), 8(7):64. DOI:10.3390/cancers8070064 Suzman DL, Luber B, Schweizer MT, et al (2014). Clinical activity of enzalutamide versus docetaxel in men with castration-resistant prostate cancer progressing after abiraterone. Prostate, 74(13):1278-1285. DOI:10.1002/pros22844 Tagawa ST, Milowsky MI, Morris M, et al (2013). Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer. Clin Cancer Res, 19(18):5182-5191. DOI:10.1158/1078-0432.CCR- 13-0231 Tannock IF, de Wit R, Berry WR, et al (2004). Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med, 351(15):1502-1512. DOI:10.1056/nejmoa040720 Watson PA, Arora VK & Sawyers CL (2015). Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer, 15(12):701-711. DOI:10.1038/nrc4016

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