Cancer Therapy Advisor: Prostate Cancer Special Edition

SPECIAL EDITION:

Prostate Cancer A17 FEATURE

A19 FEATURE

A22 VIEWPOINT

Chemotherapy and Androgen Deprivation Therapy for PCa

Prostate Cancer Treatment Options: A Decade in Review

Trends in Treatment Selection for Low-Risk Prostate Cancer

Does timing matter in patients with advanced disease?

Reviewing the last 10 years to better understand the future.

Research shows improvement in appropriate treatment selection.

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8/12/15 10:10 AM

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In men with mCRPC who progressed on ADT

The story for ZYTIGA® has significantly evolved.

Presenting…

mCRPC = metastatic castration-resistant prostate cancer; ADT = androgen-deprivation therapy.

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Please see additional Important Safety Information on the next pages.

Please see brief summary of full Prescribing Information on subsequent pages.

Date: 07/29/15 Customer Code: 028723-150602 Group 360 Job #: 735022 File Name: 028723-150602_735022_v1a (pg 1 Right Hand Start) Brand: Zytiga® Size: 7.75" x 10.5" Colors: CMYK Description: The story for ZYTIGA® has significantly evolved.

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ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

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INDICATION

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In men with mCRPC who progressed on ADT, consider ZYTIGA® (abiraterone acetate) first.

Final analysis of the pivotal phase 3 trial.*

Every day tells a story.

*Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were OS and radiographic progression-free survival (rPFS). Select exclusion criteria included AST and/or ALT ≥ 2.5X ULN, liver metastases, moderate or severe pain, opiate use for cancer pain, and visceral organ metastases. † At a prespecified final analysis for OS, 65% (354/546) of patients treated with ZYTIGA® + prednisone compared with 71% (387/542) of patients treated with placebo + prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer. § rPFS was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 [PCWG2] criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally reviewed radiographic assessment of progression.

IIAt the prespecified rPFS analysis, 150 (28%) of patients treated with ZYTIGA® + prednisone and 251 (46%) of patients treated with placebo + prednisone had radiographic progression.

Please see brief summary of full Prescribing Information on subsequent pages.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2015 6/15 028723-150602

Date: 07/29/15 Customer Code: 028723-150602 Group 360 Job #: 735022 File Name: 028723-150602_735022_v1a (pg 2 Left Hand) Brand: Zytiga® Size: 7.75” x 10.5” Colors: CMYK Description: The story for ZYTIGA® has significantly evolved.

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Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

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IMPORTANT SAFETY INFORMATION

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In the final analysis…

ZYTIGA® (abiraterone acetate) + prednisone achieved a median overall survival (OS) of almost 3 years (34.7 months).1† • 4.4 months improvement in median OS—34.7 months with ZYTIGA® + prednisone vs 30.3 months with placebo + prednisone (active compound)‡ Co-primary end point—median OS: hazard ratio (HR)=0.81; 95% CI: 0.70, 0.93; P=0.0033.

Co-primary end point—rPFS: median not reached for ZYTIGA® + prednisone vs a median of 8.28 months for placebo + prednisone; HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.§II

With a median 49 months of follow-up, there were no notable changes in the safety profile of ZYTIGA® + prednisone since the previously reported interim analyses.1 In your patients with mCRPC…

CONSIDER ZYTIGA® FIRST.

034441-150514

Learn more today at

www.zytigahcp.com.

Every day tells a story.

Date: 07/29/15 Customer Code: 028723-150602 Group 360 Job #: 735022 File Name: 028723-150602_735022_v1a (pg 3 Right Hand) Brand: Zytiga® Size: 7.75” x 10.5” Colors: CMYK Description: The story for ZYTIGA® has significantly evolved.

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Reference: 1. Ryan CJ, Smith MR, Fizazi K, et al; for the COU-AA-302 Investigators. 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. 2015;16(2):152-160.

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Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%.

Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In a CYP2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA®. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA®.

Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information].

In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions].

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

ZYTIGA® (abiraterone acetate) Tablets Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3

ZYTIGA® (abiraterone acetate) Tablets 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia,

Musculoskeletal discomfort, and Musculoskeletal stiffness terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable.

Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 4 Includes

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo.

The median duration of treatment with ZYTIGA was 13.8 months.

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0

ZYTIGA® (abiraterone acetate) Tablets Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%).

Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.

Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine).

If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate.

Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see Clinical Pharmacology (12.3) in full Prescribing Information].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information.

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].

Based on its mechanism of action, ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.

• Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone.

• Patients should be informed that ZYTIGA should not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions.

• Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions.

• Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.

• Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

Geriatric Use: Of the total number of patients receiving ZYTIGA in Phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 ©Janssen Biotech, Inc. 2012 Revised: May 2015 034443-150514

EDITORIAL & BUSINESS STAFF Managing Editor, Haymarket Oncology Lauren Burke

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FEATURE Better Survival with ADT plus Raditaion Therapy for Locally Advanced Prostate Cancer JODY A. CHARNOW

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VIEWPOINT The Identification of Genetic Anomalies May Aid Treatment in 90% of Prostate Cancers

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FEATURE

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Androgen Deprivation Therapy and Chemotherapy for Prostate Cancer: Does Timing Matter?

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FEATURE Dramatic Change in the Treatment of Prostate Cancer: A Review of the Past Decade JOHN SCHIESZER

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VIEWPOINT Improvements Seen in the Management of Localized Prostate Cancer

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LATEST NEWS

Late night shift work showed no link to incidence of prostate cancer in industrial workers, according to a cohort study in a German chemical factory published in the journal Deutsches Ärteblatt International.

Evidence showing a possible carcinogenic link between late shift work and prostate cancer has been inconsistent.

Researchers studied a cohort of 27,828 men who spent at least a year working as industrial production workers between 1995 and 2005.

Potential confounders such as age, task, and employment duration were taken into consideration. The differences between the risk in daytime workers as compared with shift workers were analyzed with the Cox regression model.

There were 146 new cases of prostate cancer in 12,609 rotating shift workers and 191 in 15,219 daytime workers.

Median birth year was 1960 and 1959, respectively.

While both groups of workers demonstrated a higher incidence in prostate cancer than the rest of the population, the shift workers did not have an elevated hazard ratio (HR) for prostate cancer when compared to the daytime workers (HR=0.93, 95% CI: 0.73-1.18). Some differences were noted depending on tumor stage.

Biomarker Signatures Linked to Ethnicity May Predict Prostate Cancer Risk Ethnic disparities in prostate cancer outcomes between African American and European American patients can partially be explained by genetic/biologic factors, according to an article in the Journal of Clinical Oncology.

A total of 154 African American and European American patients from four medical centers were matched according to the Cancer of the Prostate Risk Assessment postsurgical score within each institution.

The distribution of mRNA expression levels of 20 validated biomarkers reported to be associated with prostate cancer initiation and progression was compared with ethnicity.

Of the 20 biomarkers examined, six showed statistically significant differential expression between groups: ERG (P<0.001), AMACR (P<0.001), SPINK1 (P=0.001), NKX3-1 (P=0.03), GOLM1 (P=0.03), and androgen receptor (P=0.04).

Dysregulation of GOLM1 (P=0.037), SRD5A2 (P=0.023) predicted clinical outcomes, including 3-year biochemical recurrence and metastasis at 5 years. A greater proportion of African American men than European American men had triple-negative (ERG-/ETS-/SPINK1-negative) disease (51% vs 35%; P=0.002).

Abiraterone-Prednisone Does Not Affect Sipuleucel-T Immune Response Screening for prostate cancer has declined significantly among men older than 50 after the USPSTF guideline that discouraged prostate-specific antigen (PSA)-based screening, according to a study published in the Journal of Clinical Oncology.

M ichael Drazer, BS, and fellow researchers of The University of Chicago Medical Center in Chicago, IL, conducted a trend analysis to determine the population-based impact of the 2012 recommendation.

“Previous USPSTF recommendations did not appreciably alter prostate cancer screening,” the authors noted.

Looking through the National Health Interview Survey to estimate the proportion of men age 40 and older who were screened for prostate cancer in 2013, they used an externally validated 9-year mortality index to analyze screening rates.

They found that while PSA-based screening did not significantly change from 2010 to 2013 for men age 40 to 49, they significantly declined in men age 50 to 59, 60 to 74, and 75 or older.

In addition, a large percentage of men were screened despite high-risk of nine-year mortality, including about one-third of men older than 75.

About 1.4 million men age 65 or older with high-risk of nine-year mortality were screened in 2013.

Androgen Receptor Splice Variant 7 May Serve as Treatment Biomarker in Prostate Cancer Circulating tumor cell (CTC)-based androgen receptor splice variant 7 (AR-V7) detection may serve as a treatment selection biomarker in men with castration-resistant prostate cancer (CRPC), according to results of a study published in JAMA Oncology.

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No Link Between Shift Work, Prostate Cancer Incidence, Study Shows

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Study Characterizes Molecular Profile of Neuroendocrine Prostate Cancer Neuroendocrine prostate cancer is characterized by a molecular profile defined by distinct genomic alterations and decreased androgen receptor signaling.

Patients with neuroendocrine prostate cancer often have an aggressive clinical course and poor overall survival due to androgen receptor independence. In a study, researchers performed whole-exome sequencing of 124 metastatic tumors from 81 patients. Of those, 35 had morphological features of neuroendocrine prostate cancer.

Results showed that the mutational landscape of castrationresistant prostate cancer and neuroendocrine prostate cancer did not significantly differ in the rate of nonsynonymous mutations or copy number burden; however, RB1 loss (70% vs 32%; P=0.003) and TP53 mutation or deletion (66.6% vs 31.4%; P=0.04) were more common in neuroendocrine prostate cancer than castration-resistant disease.

The study also demonstrated that there was decreased androgen receptor signaling in neuroendocrine prostate cancer and a range of androgen receptor signaling in castrationresistant disease. Androgen receptor point mutations were absent in neuroendocrine disease and androgren receptor

amplification was higher and more focal in castration-resistant disease (P=0.0075).

The findings ultimately provide new insight into neuroendocrine prostate cancer biology, heterogenicity, and tumor evolution.

Adjuvant Chemo Improves Survival in High-Risk, Localized Prostate Cancer For high-risk, localized prostate cancer, adjuvant chemotherapy improved the overall survival from 89% to 93% at 4 years.

“Locally advanced or high-risk localized prostate cancer has a relatively poor prognosis,” Howard M. Sandler, MD, MS, FASTRO, chair of Radiation Oncology at Cedars-Sinai Medical Center in Los Angeles, CA, said.

“Standard management often uses radiotherapy and long-term hormonal treatment, but improvement in local and systemic treatment are likely to be beneficial.”

For the study, researchers enrolled 612 patients with highrisk, localized prostate cancer with a median age of 66 years and a median prostate-specific antigen (PSA) of 15.1.

Patients were assigned to receive androgen suppression plus radiotherapy with or without adjuvant docetaxel and prednisone.

Results showed that among 563 evaluable patients, the 4-year overall survival rate was 89% (95% CI: 84, 92) for the androgen suppression plus radiotherapy arm and 93% (95% CI: 90, 96) for the chemotherapy arm (HR=0.70; 95% CI: 0.51, 0.98; P=0.04), with a median follow-up of 6 years.

Speaking on the importance of the trial, Dr. Sandler said, “For the first time, [we are seeing] improvement in overall survival with tolerable adjuvant chemotherapy for localized, high-risk, hormone-sensitive prostate cancer. In addition, the cumulative incidence of distant metastases was reduced.”

Additional follow-up is warranted to evaluate the long-term benefit of chemotherapy compared with the standard of care of long-term active surveillance plus radiotherapy.

Prostate Cancer Working Group Updates CRPC Clinical Trial Guidelines The Prostate Cancer Working Group 3 (PCWG3) recommendations will guide clinical trial design and conduct for

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Previous research has demonstrated the AR-V7 was associated with primary resistance to enzalutamide or abiraterone therapy. For this study, researchers sought to investigate whether AR-V7 status would have an impact on chemotherapy sensitivity.

Researchers enrolled 37 patients with metastatic CRPC initiating treatment with docetaxel or cabazitaxel at The Johns Hopkins Hospital in Baltimore, MD. Of those, 17 had detectable AR-V7 in CTCs. Results showed that PSA responses occurred in both AR-V7-positive and AR-V7-negative patients (P=0.019), and PSA progression-free survival (P=0.32) and progression-free survival (P=0.11) were similar in both AR-V7-positive and AR-V7-negative men.

The study also demonstrated superior clinical outcomes with taxanes compared with enzalutamide or abiraterone in AR-V7-positive patients, while outcomes in AR-V7-negative men did not differ by treatment type.

In AR-V7-positive men, PSA responses were higher in taxane-treated men (P<0.001), and PSA progression-free survival (P=0.001) and progression-free survival (P=0.003) were significantly longer.

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Digital Rectal Exams Have Limited Value for Prostate Cancer Screening Digital rectal examinations (DREs) have questionable utility for detecting clinically significant prostate cancer (PCa) in men with normal prostatespecific antigen (PSA) values. In some cases, the risks associated with the DRE and follow-up testing may outweigh its benefits, according to investigators.

Tao Cui, MD, and colleagues from Wake Forest Baptist Medical Center in Winston-Salem, NC, analyzed data from 35,873 men who participated in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening trial.

These men received 129,028 PSA tests and 124,694 DREs over the first three years after randomization. Dr. Cui’s

group evaluated the ability of the DRE to detect clinically significant PCa in the settings of normal PSA (less than 4 ng/mL) and abnormal PSA. The researchers defined clinically significant disease as intermediate-risk or higher (based on NCCN guidelines) in men younger than 75.

Among men with normal PSA and abnormal DRE, 19.2% were found to have any prostate cancer. To detect one case of clinically significant prostate cancer not detected by PSA, 1,372 men needed to be screened with DRE. While DREs do capture a few additional cases of clinically significant disease among men with normal PSA, its independent value appears limited.

“If PSA is normal and DRE is considered abnormal, the chance of clinically significant cancer may not be any higher than if both DRE and PSA were normal,” Dr. Cui said. “We are not necessarily advocating for complete dismissal of the DRE, but this study sheds some light on its utility.”

The researchers noted that the exam itself is invasive and subjects a large number of men to discomfort for relatively minimal gain. “In our experience, we have encountered some patients that specifically cite the DRE as a reason why they avoid going to a physician,” Dr. Cui said.

Post-Prostatectomy Outcomes Differ for Gleason 8 and 9 or 10 Prostate Cancer Patients with Gleason 9 or 10 prostate tumors have worse oncologic outcomes after radical prostatectomy (RP) than those with Gleason 8 tumors according to research.

Weichen Xu, MD, and colleagues at the University of Southern California in Los Angeles, CA, studied 360 RP patients found to have Gleason 8, 9, or 10 prostate tumors on final pathology.

Compared with patients who had Gleason 8 cancer, those with Gleason 9 or 10 tumors had a significant 60% increased risk of biochemical recurrence and 1.9 times increased risk of clinical recurrence, after controlling for preoperative prostate-specific antigen level, pathologic stage, use of adjuvant radiotherapy, and use of neoadjuvant or adjuvant hormone deprivation therapy. Overall survival did not differ significantly between the groups.

The study population had a median age of 66 years. The median follow-up for the Gleason 8 and Gleason 9 or 10 patients was 10.0 and 8.6 years, respectively.

Of the 360 patients, 227 and 133 patients had Gleason 8 and Gleason 9 or 10 tumors. Significantly fewer patients with

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therapeutics being tested in both M0 and M1 castration-resistant prostate cancer (CRPC) patient populations, according to a consensus criteria update.

The criteria are based on evidence from clinical trial data and validation studies of PCWG2 guidelines.

“PCWG3 considers all aspects of the clinical trial process from discovery to validation in a biomarker context,” said Howard I. Scher, MD, chair of PCWG3.

With respect to eligibility, the PCWG3 defines clinical phenotypes and molecular genotypes for risk stratification and to predict likelihood of response to treatment.

Furthermore, the PCWG3 revised a clinical states model to account for the effect of prior therapy/therapies on disease biology.

In regard to the intervention aspect of the clinical trial, the guidelines state that there should be proof of mechanism, dose, and schedule. Pharmacodynamic measures should be used to confirm the mechanism of action, and dose and schedule should be optimized for further study based on biologic markers and safety.

The PCWG3 recommendations add a new facet to outcomes and endpoints: symptomatic skeletal events. In addition to evaluating clinical benefit, symptomatic skeletal events, which is inclusive of palliative radiation or surgery to bone, spinal cord compression, or pathologic clinical fracture, should be included as an endpoint.

For patients transitioning from M0 to M1 disease, metastasis-free survival and radiographic progression-free survival should be used as endpoints, as well.

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Radical Prostatectomy Offers Excellent Long-Term Outcomes Radical prostatectomy (RP) is associated with excellent long-term outcomes in patients with localized prostate cancer (PCa), according to researchers.

In a study of 529 patients with PCa who underwent RP from 1985 to 1994, Giorgio Gandaglia, MD, of IRCCS Ospedale San Raffaele in Milan, Italy, and colleagues found that overall 20-year rates of biochemical recurrence (BCR)-free, clinical recurrence-free, and cancer-specific survival were 55.1%, 71.6%, and 78.2%, respectively.

The median follow-up for survivors was 168 months. The 5-year BCR-free survival rates increased according to the time elapsed between surgery and patient evaluation: the rates were 87.3%, 89.2%, 89.5%, 92.0%, and 92.5% when the time elapsed was 1, 2, 3, 4, and 5 years, respectively. The median time from BCR to cancer-specific mortality (CSM) was 79 months.

In multivariate analysis, time from surgery to BCR was a significant predictor of CSM. Patients experiencing BCR 10 years after surgery remained at higher risk of CSM compared with their counterparts free from recurrence at the same point, even after adjusting for the risk of other-cause mortality.

CSM rates increased along with D’Amico risk groups and age. For example, the rate was 3.3% for low-risk patients younger than 65 and 30.9% for high-risk patients 65 and older.

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Surgical Margin Status Has No Effect on Prostate Cancer Survival Positive surgical margins (PSMs) alone do not influence overall survival among patients with prostate cancer undergoing radical prostatectomy (RP), according to investigators at the 2015 American Urological Association annual meeting.

Alexa Meyer, MD, and collaborators at Columbia University in New York, NY, identified 3,252 patients who underwent RP. The group included 830, 1,746, and 676 patients with low-, intermediate-, and high-risk disease, respectively. The median follow-up was 94.2 months.

While the overall PSM rate was 26.8%, it was 14.6%, 27.5%, and 39.9% in the low-, intermediate-, and high-risk groups,

respectively. The overall median survival was significantly lower for the PSM group than the negative margin group (20.14 vs 20.58 years).

The median survival also differed significantly among the three risk groups. It was 20.33 and 19.52 years for the intermediate- and high-risk groups, respectively, and was not yet reached for the low-risk group. Within each risk group, however, PSMs had no impact on survival.

When controlling for adverse features, PSMs are not independently associated with survival, the researchers concluded.

“This suggests that margin status is a surrogate for established risk criteria and disease biology, and should not be interpreted as a unique prognostic factor," Dr. Meyer said.

Elevated Neutrophil-Lymphocyte Ratio Linked to Worse Prostatectomy Outcomes An elevated neutrophil-lymphocyte ratio (NLR) prior to radical prostatectomy for prostate cancer is significantly associated w it h h igher rates of biochem ical recurrence and positive surgical margins, according to recent data.

Compared with patients who have an NLR below 5, those with an NLR above 5 have a significant 13% increased risk of biochemical recurrence at 10 years.

Vidit Sharma, MD, of Mayo Clinic in Rochester, MN, and colleagues identified 8,350 RP patients who had a median follow-up of 9.7 years. Of these, 1,568 (18.7%) had a pre-RP NLR above 5.

These patients were significantly more likely than those with an NLR below 5 to have pT3/4 disease at RP (22% vs 17.1%) and positive surgical margins (33.2% vs 25.8%) and significantly more likely to receive adjuvant hormonal therapy (13.8% vs 8.2%) and radiation therapy (4.7% vs 3.2%).

Patients with an NLR above 5 also were significantly more likely to receive salvage hormonal therapy during follow-up (14% vs 11.4%).

After controlling for age, Gleason score, preoperative PSA level, pathologic state, and use of adjuvant hormonal or radiation therapy, an NLR above 5 remained a significant predictor of biochemical recurrence, according to investigators.

An elevated NLR is a marker of systemic inflammation that is associated with adverse outcomes in multiple malignancies.

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Gleason 8 tumors than patients with Gleason 9 or 10 tumors had non-organ-confined disease (55.1% vs 71.4%).

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FEATURE

BY JODY A. CHARNOW

R

ecently published studies provide additional evidence supporting the use of combination treatment with androgen deprivation and radiation in patients with locally advanced prostate cancer (PCa).

The studies demonstrate that androgen deprivation therapy (ADT) plus radiation therapy (RT) is associated with superior cancer-specific and overall survival compared with ADT alone, prompting researchers to conclude that ADT plus RT is a reasonable option for treating locally advanced PCa. “For patients [with locally advanced PCa] who are treated by radiation, the standard of care should be ADT plus RT. Period,” said Justin E. Bekelman, MD, associate professor of radiation oncology at the University of Pennsylvania in Philadelphia, PA. “The challenge is, there’s never been a trial that has compared surgery to ADT plus RT for locally advanced prostate cancer.

That trial is crucial. That would fill the evidence gap.” At his institution, RT plus long-term ADT is the standard recommendation for patients with locally advanced PCa who opt for RT, he said.

Manageable Side Effects “I think that the important thing to note is that the combination of

Some researchers believe this approach is, or should be, the standard of care, although it remains unclear how it compares with surgery.

radiation with hormone therapy not only improves lives, but is tolerable, Dr. Bekelman said. “With modern radiotherapy techniques, studies have shown that the side effects of radiation with hormone therapy are manageable.”

Dr. Bekelman led a study comparing ADT alone and ADT plus RT in three groups of men with locally advanced or high-risk PCa.1 These groups included a cohort of 4,642 men age 65 to 75 in a randomized controlled trial (RCT); an elderly cohort of 8,694 men older than 75 with locally advanced PCa; and a cohort of 2,017 men age 65 and older with screen-detected high-risk PCa. In the RCT cohort, ADT plus RT was associated with a significant 57% decreased risk of cancer-specific mortality and 37% decreased risk of all-cause mortality compared with ADT alone in propensity score-adjusted analyses. In the elderly cohort, ADT plus RT was associated with a significant 49% and 37% decreased risk of cancer-specific and all-cause mortality, respectively. In the screen-detected cohort, ADT plus RT was associated with a significant 75% and 50% decreased risk of cancer-specific and all-cause mortality, respectively.

In a separate study, results showed that men with locally advanced PCa treated with ADT plus RT had a significant 30% decreased risk of allcause mortality and 54% decreased risk of PCa mortality compared with

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Better Survival with ADT plus Radiation Therapy for Locally Advanced Prostate Cancer

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FEATURE

those who received ADT alone.2 The study included 1,205 men with locally advanced PCa who, from 1995 to 2005, were randomly assigned to receive ADT alone (602 men) or ADT plus RT (603 men). After a median follow-up time of 8 years, 465 patients had died, 199 from PCa. The researchers noted that patients in the combination arm experienced a higher frequency of adverse events related to bowel toxicity, but only two of 589 patients had grade 3 or higher diarrhea at 24 months after RT. Comparing Radiotherapy With Surgery Malcolm Mason, MD, of Cardiff University School of Medicine in Cardiff, England, told Cancer Therapy Advisor that he believes ADT plus RT is the standard of care for locally advanced PCa. “This is sometimes a contentious area in that the results of surgery in properly selected men treated in expert centers are undoubtedly excellent, too, though there is no level 1 evidence to support this,” he said.

Dr. Mason added, “We badly need a trial of radiotherapy plus hormones versus surgery in locally advanced disease, but the challenges in doing such a trial are formidable. Our trial and others are sometimes interpreted as indicating that curative local therapy is effective in men with locally advanced disease, whatever form of curative therapy is employed.

Now, this may be true, but it is an assumption, and it is not the only possible explanation for our study results.”

In a study of men with clinically node-positive (cN+) PCa, researchers led

by Jason A. Efstathiou, MD, DPhil, of the Department of Radiation Oncology at Massachusetts General Hospital in Boston, MA, found that ADT plus RT was associated with a significant 50% decreased risk of 5-year all-cause mortality compared with ADT alone in propensity score-adjusted analyses.3

There is a need for a trial of radiotherapy plus hormones versus surgery in locally advanced disease.

implications for clinical practice guidelines and staging systems.”

Prior to propensity score matching, 47.1% of patients who received ADT alone and 25% of those treated with ADT plus RT died within the 5-year follow-up period. The crude 5-year overall survival rate was significantly lower in the ADT-only group compared with the ADT plus RT group (49.4% vs 72.4%).

The men had a median age of 66. The median follow-up time was 5.2 years for patients diagnosed from 2004 to 2006 and 2.7 years for those diagnosed from 2004 to 2011.

Data showed that the use of ADT alone decreased from 36.6% in 2004 to 32.2% in 2011, whereas use of ADT plus RT increased from 45.2% to 54.1%. ■ References

This study included 3,540 men with cN+ PCa identified using the National Cancer Data Base. Of these, 1,818 (51.4%) received ADT plus RT, 1,141 (32.2%) received ADT alone, 220 (6.2%) received RT alone, and 361 (10.2%) received neither ADT nor RT. The propensity score-adjusted analysis, which was performed to balance baseline characteristics, included 318 ADT-only recipients matched to 318 ADT plus RT recipients.

1. Bekelman JE, Mitra N, Handorf EA, et al.

Effectiveness of androgen-deprivation therapy and radiotherapy for older men with locally advanced prostate cancer. J Clin

Oncol. 2015;33(20):716-722.

2. Mason MD, Parulekar WR, Sydes MR, et al.

Final report of the intergroup randomized study of combined androgen-deprivation therapy plus radiotherapy versus androgen-deprivation therapy alone in locally advanced prostate cancer. J Clin Oncol.

2015;33(10):2143-2150.

Important Clinical Implications “As aggressive local management of cN+ prostate cancer may lead to durable disease control and even cure,” the authors concluded, “these data have important

3. Lin CC, Gray PJ, Jemal A, Efstathiou JA. Androgen deprivation with or without radiation therapy for clinically node-positive prostate cancer. J Natl Cancer Inst. 2015; 107(7): pii: djv119.

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VIEWPOINT | BY JOHN SCHIESZER

The Identification of Genetic Anomalies May Aid Treatment in 90% of Prostate Cancers An international study finds that genetic counseling may aid in determining treatment options for patients.

I

t may soon be easier to treat metastatic castration-resistant prostate cancer (mCRPC) based on genetic anomalies. As an international study suggested it may be possible to link specific aberrations to response or resistance to specific treatments in 90% of cases.

Researchers from eight institutions in the United States and in Europe collaborated and sequenced the DNA and RNA of tumor biopsy samples from 150 men with mCRPC. They found that patients with mCRPC harbor genomic alterations in PIK3CA/B, RSPO, R AF, APC, B-catenin, and ZBTB16 and 23% harbor DNA repair pathway aberrations.1 “We were surprised that upwards of 90% of patients with advanced prostate cancer have clinically actionable aberrations. Not including androgen receptor (AR) as a target, over 60% of patients have actionable aberrations in other pathways. This suggests that precision medicine approaches may be especially important in patients with metastatic disease,” said principal study investigator Arul Chinnaiyan, MD, PhD, professor of pathology at the University of Michigan Health System in Ann Arbor, MI. He said t he results f rom t his study showed that clinical genomic sequencing could impact treatment

decisions in a significant number of patients with metastatic disease.

Prev ious st udies have examined the genomic landscape of clinically localized prostate cancer and found few actionable genomic alterations.

However, that does not appear to be the case with this specific clinical subtype.

The study demonstrated that AR, ETS genes, and TP53 and PTEN alterations

Approximately 90% of patients with advanced PC have clinically actionable aberrations. were present in 40% to 60% of cases. In addition, AR and TP53 alterations were enriched in cases of metastatic disease compared to primary prostate cancer.

“I was surprised that we could successfully generate cancer genome data from most patients. There was a lot of skepticism in advance because these biopsies, particularly of bone lesions, are not straightforward,” study investigator Charles Sawyers, MD, told Cancer Therapy Advisor.

Dr. Sawyers, who is the chair of the Human Oncology and Pathogenesis

Program at Memorial Sloan Kettering Cancer Center in New York, N Y, said until now precision medicine activities in advanced prostate cancer have been limited for several reasons.

He said there has been a lack of ability to acquire clinical samples from patients at the time of failure of hormone treatment. In addition, Dr. Sawyers said there has been a lack of comprehensive genomic data for potentially actionable alterations.

This multi-institutional and international study demonstrated the feasibility of comprehensive and integrative genomics on prospective biopsies from individual patients to enable precision cancer medicine activities. He said this study sets the stage for additional profiling efforts that may enable biologic discovery and have immediate therapeutic relevance.

Researchers indicated that nearly twothirds of the patients in the study had aberrations in the AR and 14% had a mutation in the BRCA1 or BRCA2 gene.

Mutations in these two BRCA genes are already known to increase breast and ovarian cancer risk. Poly (ADP-ribose) polymerase (PARP) inhibitors have already been approved in BRCA-positive ovarian cancer, and these new findings suggest PARP inhibitors could be effective in some prostate cancers. “We found that over 20% of patients with mCRPC had mutations in DNA repair pathway genes such as BRCA2 and BRCA1.

This would suggest that this subset of patients may benefit from PARP inhibitors or platinum-based therapies,” Dr. Chinnaiyan told Cancer Therapy Advisor.

The study showed that 8% of patients had an inherited genetic alteration, suggesting genetic counseling may be appropriate for pat ients wit h metastatic prostate cancer. A unique Continued on page A21

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Androgen Deprivation Therapy and Chemotherapy for Prostate Cancer: Does Timing Matter?

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ecent reports may help inform clinical decision making with respect to the timing of androgen deprivation therapy (ADT) and chemotherapy in patients with recurrent or advanced prostate cancer (PCa).

According to results of a study led by Stephen J. Freedland, MD, of CedarsSinai Medical Center in Los Angeles, CA, early ADT may increase the risk of death among men who receive it after experiencing biochemical recurrence (BCR) of PCa following radical prostatectomy.1 This adverse effect appears to be limited to men younger than 65 when they experience BCR and those with low-risk disease. The study retrospectively analyzed data from 468 patients who experienced BCR after radical prostatectomy. The median follow-up after BCR was 70 months. Of the 135 men who received early ADT (defined as receipt of ADT when prostate-specific antigen [PSA] levels were less than 5 ng/mL), 42 died. In adjusted analyses, early ADT was associated with a 68% increased risk of death compared with the 333 men who received conventional therapy (no ADT or ADT started when PSA levels were 5 ng/mL or higher). When the researchers stratified the men by age, early ADT was associated with a 5.6 times increased risk of death compared with conventional

Earlier androgen deprivation therapy may increase death risk in men who receive it after a biochemical recurrence, but earlier docetaxel may lower it.

therapy among men younger than 65, and a 61% decreased risk among those 65 and older. Early ADT was associated with a 3.2 times increased mortality in patients with low-risk disease, but it did not significantly affect survival in those with high-risk disease.

Finally, the data suggest that men with a PSA doubling time of less than 9 months fared better with early ADT, whereas those with longer PSA doubling times fared worse. While presenting their research at the American Urological Association (AUA) 2015 annual meeting in New Orleans, LA, Dr. Freedland’s team concluded that the “risks and benefits of ADT must be weighed and taken into account when deciding timing of treatment.” Whether the harmful effect of early ADT is due to true harm, treatment bias, or unmeasured confounding factors is not known, they noted.

Dr. Freedland told Cancer Therapy Advisor that ADT should be used selectively for those with the highest risk of death from PCa. Salvage ADT In a separate study presented at the AUA 2015 annual meeting, researchers found that delaying salvage ADT in patients with PCa who experience BCR after brachytherapy did not adversely impact all-cause or cancer-specific survival. 2 A total of 115 men who received brachytherapy and experienced

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biochemical failure according to the Phoenix definition were included.

The investigators stratified patients by receipt of immediate or delayed ADT and by receipt of ADT at a PSA threshold of 10 ng/mL. Forty men had immediate ADT and 75 had delayed ADT (3 or more months after recurrence was identified). During a median follow-up of 11.5 years, 56 patients died, 37 from PCa. Patients receiving immediate ADT had higher PSA levels at failure than the delayed ADT group (11.6 vs 5.6 ng/mL). The median delay to salvage ADT was 1.8 years. Delayed ADT and a PSA threshold of 10 were not significantly associated with allcause or cancer-specific mortality.

Earlier Docetaxel Beneficial In a study presented at the 2015 American Society of Clinical Oncology annual meeting in Chicago, IL, researchers found that administering docetaxel chemotherapy at the same time as starting long-term hormone therapy for the first time can improve survival in men with high-risk locally advanced or metastatic PCa.3 In this study, 2,962 patients (61% with metastatic disease) were randomly assigned to one of four treatment arms: standard of care (SOC), SOC plus docetaxel, SOC plus zoledronic acid, and SOC plus docetaxel and zoledronic acid. The median follow-up was 42 months. Compared with patients in the SOC-only group, those in the SOC plus docetaxel group and SOC plus docetaxel and zoledronic acid group had a 24% and 19% decreased risk of death, respectively. Survival did not differ significantly among patients in the SOC plus zoledronic acid group. Median survival in the SOC-only group was 67 months compared with 77 among subjects in the SOC plus docetaxel group.

Continuous Versus Intermittent ADT In another study that could help guide patient management, researchers documented that intermittent and continuous ADT were associated with similar efficacy, tolerability, and quality of life among patients with relapsing or locally advanced PCa.4 In a prospective phase 3b open-label study, 701 patients with locally advanced or relapsing nonmetastatic PCa after radical prostatectomy or radiotherapy were randomly assigned to receive either continuous or intermittent ADT with leuprorelin for 36 months. Inclusion criteria required a Gleason score of 6 or higher and a life expectancy of 5 years or more.

A total of 58% of patients had locally advanced PCa, and 42% had relapsing nonmetastatic PCa. The continuous and intermittent groups were comparable at baseline. Patients were followed at 6-month intervals for 18 months. Results showed that time to PSA progression

when the researchers compared AEs in patients with locally advanced PCa versus relapsing PCa at baseline, they found no differences between continuous or intermittent ADT with respect to the number of AEs, serious AEs, or AEs leading to drug discontinuation.

Conclusion Recent studies in patients with PCa evaluating the effects of early ADT, salvage ADT, early administration of docetaxel, and continuous versus intermittent administration of ADT have shed some light on the best treatment options in different PCa patient populations, and may offer a guide for patient therapy in the future. Further studies are still required to optimize outcomes of patients with PCa. â&#x2013; References 1. Freedland S, Howard L, Amling C, et al. Does early androgen therapy after biochemical recurrence following radical prostectomy increase overall survival? Results from SEARCH [abstract MP82-15]. Presented at the American Urological Association 2015

Intermittent and continuous ADT were associated with similar efficacy and tolerability.

annual meeting.

2. Sagalovich D, Leapman M, Sfakianos, et al. Timing of salvage androgen deprivation therapy following prostate radiotherapy does not adversely affect all-cause or prostate cancer specific survival [abstract MP87-04]. Presented at the American Urological Association 2015 annual meeting.

3. James ND, Sydes MR, Mason MD, et al.

(the primary endpoint), PSA progression-free survival, mean PSA levels over time, quality of life, and overall survival did not differ significantly between the groups. The estimated 5-year overall survival rates for the continuous and intermittent ADT groups were 85% and 81.8%, a nonsignificant difference.

Most adverse events (AEs) were mild or moderate; the most common were hot flushes and hypertension. In addition,

Docetaxel and/or zoledronic acid for hormonenaĂŻve prostate cancer: first overall survival results from STAMPEDE (NCT00268476).

J Clin Oncol. 2015;33 (suppl; abstract 5001).

4. Schulman C, Cornel E, Matveev V, et al.

Intermittent versus continuous androgen deprivation in patients with relapsing or locally advanced prostate cancer: a phase 3b randomized study (ICELAND) [abstract MP7320]. Presented at the American Urological Association 2015 annual meeting.

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BY JOHN SCHIESZER

M

ajor treatment strategies for prostate cancer have been approved over the past decade that have dramatically increased survival rates and changed the treatment paradigm for patients with the disease, and even greater improvements are expected within the next decade.

In 2005, there were only a handful of approved prostate cancer medications.

However, today there are many more and they work by several different mechanisms, allowing them to extend life in novel ways. In 2005, the relative 10-year survival rate for prostate cancer was 92% and the relative 15-year survival rate was 61%, according to the American Cancer Society.1 Today, the numbers are significantly higher: the relative 5-year survival rate for all stages of prostate cancer is almost 100%, the relative 10-year survival rate is 99%, and the 15-year relative survival rate is 94%.2 “The greatest advances in t he management of prostate cancer in the last decade have come directly from our understanding of the biology of what causes prostate cancer cells to become resistant to treatments we had a decade ago,” said Anthony D’Amico, MD, PhD, of Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston, MA.

Drug approvals over the past decade hold hope for patients, but additional advances are needed to convert prostate cancer into a chronic disease.

He sa id t he Prost ate Ca ncer Foundation (PCF), which was formerly the Association for the Cure of Cancer of the Prostate (CaP CURE), helped usher in a new era in terms of research.

It included leading scientific and clinical experts and it helped expedite new treatments. In 2004, the U.S. Food a nd Dr ug Adm in ist rat ion ( FDA) approved doceta xel af ter the publication of two randomized controlled trials, one of which was led by a PCF clinical investigator.3 Over the past decade, the FDA has approved the pure luteinizing hor mone –releasing hor mone antagonist degarelix (Firmagon), the first immunotherapy for prostate cancer, sipuleucel-T (Provenge), and a taxane-based chemotherapy, cabazitaxel ( Jevtana). The FDA also approved denosumab (Prolia/Xgeva) as a treatment to increase bone mass in patients at high risk for fracture receiving androgen-deprivation therapy (ADT). Enzalutamide (Xtandi) has been approved to treat men with metastatic castration-resistant prostate cancer that has spread or recurred, even with medical or surgical therapy to minimize testosterone. Enzalutamide was approved for patients who have previously been treated with docetaxel.

In May 2013, the FDA approved radium Ra 223 dichloride (Xofigo) to treat symptomatic late-stage metastatic

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castration-resistant prostate cancer that had spread to bones, but not to other organs. “Provenge and radium 223 dichloride have helped a lot for patients in the late stages of the disease,” Dr. D’Amico told Cancer Therapy Advisor.

“In the future, we hope to do more than just extend life more than several months in late-stage disease.”

It is now estimated that one in seven men will be diagnosed with prostate cancer during his lifetime and approximately 220,800 new cases of prostate cancer will be diagnosed in 2015 alone.4 The American Cancer Society predicts in 2015 there will be approximately 27,540 deaths from prostate cancer.

Yair Lota n, M D, professor of urology and chief of urologic oncology at University of Texas Southwestern Medical Center in Dallas, TX, said no one agent has been a home run, even though there have been significant advances in the past decade. “The advancements of the past decade have been mostly small incremental changes. Each of the new therapies provides modest survival benefits, 3 to 4 months,” Dr. Lotan told Cancer Therapy Advisor. “There is still a desperate need for effective therapy for patients with castrate-resistant prostate cancer, and it is unclear whether this will be provided by novel targeted therapies.”

Tomasz Beer, MD, chair of prostate cancer research and the deputy director of the Oregon Health & Science University (OHSU) Knight Cancer Institute in Portland, OR, said clinicians should be cautious when analyzing the 5- and 10-year survival numbers. He said while treatment improvements are partly responsible for better outcomes, a part of this trend reflects early diagnosis and stage migration.

“Having said that, there have been major advances; the most notable of which is the development of two new dr ugs t hat target androgen receptor signaling, abiraterone and enzalutamide. But in total six agents t hat ex tend su r v ival have been approved, approximately five in the last 5 years. That is real progress,” Dr. Beer told Cancer Therapy Advisor. “Further, and importantly, we have learned that earlier use of chemotherapy in metastatic but hormone-responsive disease substantially magnified the

Despite advances, there is a need for effective therapy for castration-resistant prostate cancer. benefits of chemotherapy. Taken toget her, t he ea rly appl ic at ion of chemot her apy coupled w it h compelling new androgen receptor signaling inhibitors have transformed the management of advanced disease.”

Mea s u r i ng c i rc u lat i ng t u mor cells (CTCs) following f irst-line therapy is changing how patients are managed. This past year, researchers reported that detection of androgenreceptor splice variant 7 messenger RNA (AR-V7) in CTCs from men with advanced prostate cancer may be associated wit h resistance to enzalutamide and abiraterone.5 “The biggest changes in the landscape of advanced prostate cancer include discovery of CTCs, genetic testing on them (AR-V7), improvement in overall survival from various drugs like abiraterone, enzalutamide, radium-223,

sipuleucel-T, and cabazitaxel. The most striking data are from the ECOG-3805 trial, which changed the standard of care for de novo metastatic prostate cancer by adding six cycles of docetaxel to ADT. This significantly changed the overall survival,” said Saby George, MD, assistant professor of oncology at Roswell Park Cancer Institute in Buffalo, NY. Novel agents that work by different mechanism and are matched to genetic signatures may soon significantly change the management of metastatic prostate cancer. Gerald A ndriole, MD, chief of urologic surgery at Washington Universit y School of Medicine in Saint Louis, MO, said experimental therapeutic vaccines a nd c he c k p oi nt i n h ibitor s a re showing promise and may soon be part of the armamentarium. Recently, researchers discovered that cytotoxic T lymphocyte antigen 4 (CTLA-4) is a receptor on the surface of T cells that blocks the immune response by inhibiting T cell activation. Now, studies are looking at whether an antibody (anti–CTLA-4) can block the “immune checkpoint” protein.

“More complete obliteration of the androgenic pathways has played a major role for men with advanced prostate cancer. Going for ward, efforts to better understand the role of immunotherapy with vaccines, checkpoint inhibitors, and other approaches, hold great promise, and may be applied to men with earlier stages of prostate cancer,” Dr. Andriole told Cancer Therapy Advisor.

Dr. George said there is a strong possibil it y t hat prost ate ca ncer could become a manageable chronic d isease. However, he sa id it is important that clinicians not give their patients false hope. Dr. George

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are examples of how to optimize the targeting of the androgen receptor signaling axis. There needs to be a lot more development to make this disease a chronic disease. Cure is an elusive term in advanced prostate cancer as of today,” Dr. George told Cancer Therapy Advisor. ■

More developments are needed before precision medicine makes PCa a chronic disease.

detailedguide/prostate-cancer-survivalrates. Revised March 12, 2015. Accessed July 30, 2015.

3. D’Amico AV. US Food and Drug Administration approval of drugs for the treatment of prostate cancer: a new era has begun. J Clin Oncol.

2014;32(4):362-364.

4. American Cancer Society. What are the

said many patients may mistakenly have too high of expectations based on recent reports about precision medicine and what it can and cannot do. “Precision medicine is a loose term. The clinical development of second-line hormonal manipulation like enzalutamide and abiraterone

Viewpoint

References

key facts about prostate cancer?. http://

1. American Cancer Society. Cancer facts

www.cancer.org/cancer/prostatecancer/

& figures 2005. http://www.cancer.org/

detailedguide/prostate-cancer-key-

acs/groups/content/@nho/documents/

statistics. Revised March 12, 2015.

document/caff2005f4pwsecu redpdf.pdf.

Published 2005. Accessed July 30, 2015.

2. American Cancer Society. Survival

feature of this study is that it used fresh biopsy samples from living patients with mCRPC. Typically, it has been difficult to obtain a large enough quantity of quality tumor tissue, especially from bone biopsies, to make sequencing possible.

Mark Garzotto, MD, who is an associate professor of urology and radiation medicine at Oregon Health & Science University Knight Cancer Institute in Portland, OR, said the findings are significant and could help usher in a new era in the treatment of metastatic disease. “However to advance the science further we must look beyond just the AR towards other

and resistance to enzalutamide and

rates for prostate cancer. http://www.

abiraterone in prostate cancer. N Engl J

cancer.org/cancer/prostatecancer/

Med. 2014;371(11):1028-1038.

mechanisms of cancer progression.

This will require developing effective combinations such as anti-AR therapy

Continued from page A16

Accessed July 30, 2015.

5. Antonarakis ES, Lu C, Wang H, et al. AR-V7

The ultimate goal when treating advanced prostate cancer is long-term disease control. with chemotherapy and radiation,” Dr. Garzotto told Cancer Therapy Advisor.

“Two such studies being carried out by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group aim to combine enzalutamide

with radiation for localized cancer and with standard hormone therapy for met ast at ic ca ncer. A not her combination that looks promising is anti-AR therapy with docetaxel chemotherapy,” said Dr. Garzotto.

He said “the Holy Grail” in treating cancer is long-term disease control.

That has been elusive. However, Dr. Garzotto said the trial data on the use of immunomodulators for cancer have shown that some of the most lethal cancers may be well-controlled and in some cases result in long-term survival. ■ Reference 1. Robinson D, van Allen EM, Wu Y-M, et al.

Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-1218.

Read more commentary on topics in prostate cancer at CancerTherapyAdvisor.com

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VIEWPOINT | BY SHANNON AYMES, MD

Improvements Seen in the Management of Localized Prostate Cancer Watchful waiting, active surveillance, and appropriate local treatment are key to treating prostate cancer.

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fter a history of over treatment of low-risk prostate cancer, research demonstrates an increase in watchful waiting and active surveillance, as well as appropriate local treatment for high-risk prostate cancer.

“A number of studies over the years have documented consistent over treatment of low-risk prostate cancer,” Matthew R. Cooperberg, MD, MPH, of the Helen Diller Family Comprehensive Cancer Center, told Cancer Therapy Advisor.

Studies involving data from academic centers demonstrate the safety of active surveillance with a diagnosis of lowrisk prostate cancer. However, current treatment patterns of prostate cancer in community-based practices have not been well established.

In a research letter published in JAMA, Dr. Cooperberg and Peter R. Carroll, MD, MPH, presented their study results.

Data on men with prostate cancer since 1995 was obtained from small and large urology practices in 28 states from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSUR E).

Enrollment was prospective from 1998 but was both retrospective and prospective prior to 1998.

The study participants were men with prostate tumors of stage cT3aN0M0 or lower who were treated between 1990

and 2013 with radiation, prostatectomy, monotherapy androgen deprivation, or watchful waiting/active surveillance.

The Cancer of the Prostate Risk Assessment (CAPRA) score was used to stratify the cancer risk. In men age 75 or older, treatment trends were analyzed in 5-year intervals.

With a mean age of 65.7 years (SD of 8.8 years) and median CAPR A score of 2 (range: 1 to 4), 10,472 men were included in the study. Of the participants, 87% (9,111 patients) were white and 9.7% (1,015 patients) were black.

From 1990 through 2009, active surveillance was low for low-risk prostate cancer (CAPRA score 0 to 2) and varied from 6.7% to 14.3%.

However, there was a noticeable increase to 40.4% in 2010 through 2013.

Likewise, in intermediate-risk and high-risk prostate cancer, treatment with androgen deprivation was 9.7% and 29.8% in 1990 and decreased to 3.8% and 24%, respectively.

Active surveillance of men 75 or older from 1990 through 1994 was 54.1% and declined in 2000 through 2004 to 21.9%. However, the rate of active surveillance increased in 2010 through 2013 to 76.2%.

In men 75 or older, the researchers note an increase in utilization of surgery for intermediate-risk cancer to 15.0%

and low-risk cancer to 9.5%. In highrisk cancer, 66.7% received androgen deprivation therapy.

“In 2012 the USPSTF issued a blanket ‘D’ recommendation against all PSA-based screening efforts. The recommendation was based on multiple f u nda ment a l m isi nter pret at ions of the available evidence base, but also ref lected a growing national impatience with overtreatment of low-risk prostate cancer,” said Dr. Cooperberg. “The result is that many primary care physicians no longer even offer PSA testing, and a recent paper found a 28% drop across the board in prostate cancer diagnoses since the recommendation. The problem is that this decline occurred among both low-risk tumors that did not need to be found, but also among the high-risk tumors that are potentially lethal without early identification and intervention.”

These trends may swing the opinion regarding screening back toward a smarter screening paradigm.

When asked what impact this study may have on clinical practice, Dr. Cooperberg summarized, “Hopefully we will see an ongoing increase in rates of active surveillance for lowrisk disease and aggressive management for high-risk disease. We also hope these trends will help swing the balance of opinion regarding screening back toward a smarter screening paradigm, which is what men in this country need and deserve.” ■

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