Index Patients 3& 4. Guideline Statements 10/11/2014. Enzalutamide Reduced the Risk of Death

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Nigel Rose
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//4 Prolonged Radiographic Progression-Free Survival Reduced the Risk of Death Overall ITT

4) rpfs (%) ( Enza 9 8 7 4 8 8 4 79 9 8 NYR = not yet reached; CI = confidence interval.

8 Nonvisceral Subgroup Estimated median rpfs, months (9% CI): : 4. (.8 NYR); placebo: 4. (.7.

7 4 9 8 Enza 7 4 4 9 7 9 7 7 4 Visceral Subgroup Estimated median rpfs, months (9% CI): :

NYR); placebo:. (8. NYR) Overall Surv vival (%) Hazard ratio,.7 9 (9% CI,..84) P<.

Estimated median overall survival, months (9% CI): : NYR (. NYR); placebo:. (8.

7 4 Overall Survival (%) 9 8 4 7 Enza 774 77 7 74 74 9 9 7 79 7 9 4 77 4 87 8 87 Visceral

9 NYR); placebo:.8 (.9 NYR) Overall Survival (%) Hazard ratio,.8 9 (9% CI,..) 8 P=.

Median Time to Chemotherapy Overall ITT Population Estimated median time to chemotherapy,

8 7 4 9 8 4 7 Enza 87 84 799 7 7 89 8 79 84 74 8 4 4 7 4 9 Nonvisceral Subgroup Estimated

median time to chemotherapy, months (9% CI): :. (8. NYR); placebo:. (. 9.

1 //4 Prolonged Radiographic Progression-Free Survival Reduced the Risk of Death Overall ITT Population Estimated median rpfs, months (9% CI): : NYR (.8 NYR); placebo:.9 (.7.4) rpfs (%) ( Enza NYR = not yet reached; CI = confidence interval. 4 Hazard ratio,.8 (9% CI,..) P<. 8 Nonvisceral Subgroup Estimated median rpfs, months (9% CI): : 4. (.8 NYR); placebo: 4. (.7.4) 9 Hazard ratio,.7 (9% CI,.4.) 8 P< Enza Visceral Subgroup Estimated median rpfs, months (9% CI): : NYR (.9 NYR); placebo:. (..) rpfs (%) Enza 97 rpfs (%) Hazard ratio,.8 (9% CI,..49) P<. 8 Overall ITT Population Estimated median overall survival, months (9% CI): :.4 (. NYR); placebo:. (8. NYR) Overall Surv vival (%) Hazard ratio,.7 9 (9% CI,..84) P< Enza Nonvisceral Subgroup Estimated median overall survival, months (9% CI): : NYR (. NYR); placebo:. (8. NYR) Hazard ratio,.9 9 (9% CI,.7.8) 8 P=. 7 4 Overall Survival (%) Enza Visceral Subgroup Estimated median overall survival, months (9% CI): : 7.8 (.9 NYR); placebo:.8 (.9 NYR) Overall Survival (%) Hazard ratio,.8 9 (9% CI,..) 8 P= Enza Cytotoxic Che emotherapy Free (%) Delayed Median Time to Chemotherapy Overall ITT Population Estimated median time to chemotherapy, months (9% CI): : 8. (.8 NYR); placebo:.8 (9.7.) Hazard ratio,.49 9 (9% CI,..4) P< Enza Nonvisceral Subgroup Estimated median time to chemotherapy, months (9% CI): : 8.4 (.8 NYR); placebo:. (..) 9 Hazard ratio,. (9% CI,..4) 8 P< Enza Visceral Subgroup Estimated median time to chemotherapy, months (9% CI): :. (8. NYR); placebo:. (. 9.8) Cytotoxic Chemotherapy Free (%) Cytotoxic Chemotherapy Free (%) Hazard ratio,.97 (9% CI,..4) P<. Guideline Statements Index Patients & 4 Enza Header. Index Patient Arial 48. Clinicians should offer docetaxel to patients with symptomatic, mcrpc with good performance. (Standard; Evidence Level Grade B) Clinicians may offer abiraterone + prednisone to patients with symptomatic, mcrpc with good performance status and no prior docetaxel chemotherapy. (Recommendation; Evidence Level Grade C)

2 //4 Abiraterone Mechanism of Action Abiraterone is an irreversible inhibitor of the hydroxylase and lyase activities of CYP7A, which catalyzes the conversion of C progesterone precursors to C9 adrenal androgens, DHEA and androstenedione. Header. Index Patient Arial 48. Clinicians may offer ketoconazole + steroid, mitoxantrone or radionuclide therapy to patients with symptomatic, mcrpc with good performance who do not want or cannot have one of the standard therapies. [Option; Evidence Level Grade C (ketoconazole) /B (mitoxantrone) / C (radionuclide therapy)] Clinicians should offer radium- to patients with symptoms from bony metastases from mcrpc with good performance status and no prior docetaxel chemotherapy and without known visceral disease. (Standard; Evidence Level Grade B) Patients, Stratification Treatment, N=9 CRPC with symptomatic bone metastases No known visceral metastases Radium- Prior docetaxel: Yes vs No Current bisphosphonate use: Yes vs No Total alkaline phosphatase (ALP): < U/L vs > U/L Radium Ra dichloride ( kbq/kg) = best standard of care (n=4) injections at 4-week intervals (saline) + best standard of care (n=7) centers in 9 countries Included patients with malignant lymphadenopathy up to cm Best standard of care included: local external beam radiation therapy (EBRT), corticosteroids, antiandrogens, estrogens, estramustine, or ketoconazole median OS:. months (9% Cl:.4-.8) Radium- radium Ra dichloride* Radium Ra dichloride median OS: 4.9 months (9% Cl:.9-.) * radium Ra dichloride placebo % reduction in the risk of death vs placebo (HR=.9). Radium RA dichloride injection;. Parker C, et al. N Engl J Med. ;9:-. *Plus best standard of care; *9% Cl:.8-.8 for the exploratory updated analysis. Header. Index Patient Arial 48. Clinicians should NOT offer treatment with either estramustine or sipuleucel-t to patients with symptomatic, mcrpc with good performance. (Recommendation; Evidence Level Grade C) Sipuleucel-T Sipuleucel-T should be considered ONLY for patients with asymptomatic or minimally symptomatic mcrpc (Index Patient ). Patients t in the previously discussed d IMPACT trial were allowed to have previous chemotherapy: 8% had received previous docetaxel.

//4 Header. Index Patient Arial 48. 4 Clinicians may offer treatment with abiraterone + prednisone to patients with symptomatic, mcrpc with poor performance status and no prior docetaxel chemotherapy.

unwilling to receive abiraterone + prednisone. (Option; Evidence Level Grade C) Header. Index Patient Arial 48.

the performance status is directly related to the cancer.

3 //4 Header. Index Patient Arial Clinicians may offer treatment with abiraterone + prednisone to patients with symptomatic, mcrpc with poor performance status and no prior docetaxel chemotherapy. (Option; Evidence Level Grade C) Clinicians may offer treatment with ketoconazole + steroid or radionuclide therapy to patients with symptomatic, mcrpc with poor performance who are unable or unwilling to receive abiraterone + prednisone. (Option; Evidence Level Grade C) Header. Index Patient Arial Clinicians may offer docetaxel or mitoxantrone chemotherapy to patients with symptomatic mcrpc with poor performance status and no prior docetaxel chemotherapy in select cases, specifically when the performance status is directly related to the cancer. (Expert Opinion) Clinicians may offer radium- to patients with symptoms from bony metastases from mcrpc with poor performance status and no prior docetaxel chemotherapy and without known visceral disease in select cases, specifically when the performance status is directly related to symptoms related to bone metastases. (Expert Opinion) Header. Index Patient Arial Clinicians should NOT offer sipuleucel-t to patients with symptomatic mcrpc with poor performance status and no prior docetaxel chemotherapy. (Recommendation; Evidence Level Grade C) Guideline Statements Index Patients & Bone Health Header. Index Patient Arial 48. Clinicians should offer treatment with abiraterone + prednisone, cabazitaxel or enzalutamide to patients with mcrpc with good performance status who received prior docetaxel chemotherapy. If the patient received abiraterone + prednisone prior to docetaxel chemotherapy, he should be offered cabazitaxel or enzalutamide. [Standard; Evidence Level Grade A (abiraterone) /B (cabazitaxel) /A (enzalutamide)]

4 //4 Header. Abiraterone Arial 48. A Phase III trial (COU-AA-)conducted in,9 patients who had previously received docetaxel ultimately resulted in FDA approval in this patient population,mg abiraterone daily plus prednisone mg twice daily HR =. (9% CI:.4,.77) P <. Header. Abiraterone Arial 48. Median Survival:.9 Mos. Median Survival: 4.8 Mos. All secondary endpoints, including time to PSA progression, progression-free survival and PSA response rate favored the abiraterone-treated group. de Bono et al. NEJM de Bono et al. NEJM Header. Arial 48. The Phase III AFFIRM trial, including,99 men who had received prior docetaxel chemotherapy, ultimately resulted in FDA approval in this patient population mg enzalutamide orally daily Overall survival favored enzalutamide (8.4 months v.. months). There was also statistical superiority of enzalutamide for all secondary endpoints. Scher et al. NEJM HR =. (9% CI:.9,.7) P <. 7% Reduction in Risk of Death Median Survival. Mos. (9% CI:.,.8) Median Survival: 8.4 Mos. (9% CI: 7., NYR) Scher et al. NEJM Header. Cabazitaxel Arial 48. This open-label, randomized Phase III trial included 7 patients who had received prior docetaxel mg cabazitaxel intravenously with oral prednisone every three weeks mg mitoxantrone intravenously with oral prednisone every three weeks Cabazitaxel demonstrated improved overall survival (. months v..7 months) and improved progression-free survival (.8 months v..4 months). de Bono et al. Lancet HR =.7 (9% CI:.9,.8) P <. % reduction in relative risk of death Cabazitaxel Mitoxantrone Median Survival:.7 Mos. Cabazitaxel Median Survival:. Mos. de Bono et al. Lancet 4

5 //4 Header. Index Patient Arial 48. Clinicians may offer ketoconazole + steroid to patients with mcrpc with good performance status who received prior docetaxel if abiraterone + prednisone, cabazitaxel or enzalutamide is unavailable. (Option; Evidence Level Grade C) Clinicians may offer retreatment with docetaxel to patients with mcrpc with good performance status who were benefitting at the time of discontinuation (due to reversible side effects) of docetaxel chemotherapy. (Option; Evidence Level Grade C) Header. Index Patient Arial 48. Clinicians should offer radium- to patients with symptoms from bony metastases from mcrpc with good performance status who received prior docetaxel chemotherapy and without known visceral disease. (Standard; Evidence Level Grade B) Header. Index Patient Arial 48. Clinicians should offer palliative care to patients with mcrpc with poor performance status who received prior docetaxel chemotherapy. Alternatively, for selected patients, clinicians may offer treatment with abiraterone + prednisone, enzalutamide, ketoconazole + steroid or radionuclide therapy. (Expert Opinion) Header. Index Patient Arial 48. Clinicians should NOT offer systemic chemotherapy or immunotherapy to patients with mcrpc with poor performance status who received prior docetaxel chemotherapy. (Expert Opinion) Header. Bone Health Arial 48. The following statements apply to all index patients: Clinicians should offer preventative treatment (e.g., supplemental calcium, Vitamin D) for fractures and skeletal related events to CRPC patients. (Recommendation; Evidence Level Grade C) Clinicians may choose either denosumab or zoledronic acid when selecting a preventative treatment for skeletal related events for mcrpc patients with bony metastases. (Option; Evidence Level Grade C) Zoledronic Header. Arial Acid 48. Patients in a Phase III randomized trial were given 4mg of zoledronic acid (IV) every three weeks Patients showed a % decrease in skeletal-related events. Longer therapy (up to 4 months) appears to confer continued benefit. Toxicity of this therapy may include osteonecrosis of the jaw, hypocalcemia and nephrotoxicity. Saad et al. J Natl Cancer Inst 4

Denosumab resulted in more significant hypocalcemia (% v. %). Denosumab resulted in similar rates of jaw osteonecrosis (% v.

6 //4 Header. Denosumab Arial 48.,94 patients with mcrpc received subcutaneous denosumab or zoledronic acid Header. Arial 48. Denosumab v. Zoledronic Acid Denosumab demonstrated a longer time to first skeletal-related event compared to intravenous zoledronic acid given on an every 4- week schedule (.7 months v. 7. months). Denosumab resulted in more significant hypocalcemia (% v. %). Denosumab resulted in similar rates of jaw osteonecrosis (% v. %) Denosumab offers slightly superior efficacy compared to zoledronic acid, and should, therefore, be the first option. Fizazi et al. Lancet Fizazi et al. Lancet Acknowledgements CRPC Panel Michael S. Cookson, MD (Chair) Adam S. Kibel, MD (Vice Chair) Philipp Dahm, MD, MHSc Christine Engstrom, PhD, CRNP, AOCN Stephen J. Freedland, d MD Maha Hussain, MD, FACP Daniel W. Lin, MD William T. Lowrance, MD William K. Oh, MD David F. Penson, MD Bruce J. Roth, MD Methodology Hassan Murad, MD, MPH Osama Altayar, MD Mohammed Nabhan, MD AUA Guidelines Staff External Reviewers

American Urological Association (AUA) Guideline

American Urological Association (AUA) Guideline 1 Approved by the AUA Board of Directors April 2014 Authors disclosure of potential conflicts of interest and author/staff contributions appear at the end of the article. 2014 by the American Urological