Suthan Chanthawong. B. Pharm, BCP, BCOP. Faculty of Pharmaceutical Sciences, Khon Kaen University

Transcription

1 Suthan Chanthawong B. Pharm, BCP, BCOP Faculty of Pharmaceutical Sciences, Khon Kaen University

2 Objectives 1) Outline appropriate screening and prevention strategy. 2) Describe appropriate patient-specific therapy and monitoring for a stage of disease. 3) Apply the clinical data underlying therapeutic treatment recommendations. 4) Explain expected outcomes to a given therapeutic modality in terms of response and toxicity or other endpoints (e.g., survival, clinical benefit, etc.).

3 Objectives 5) Discuss supportive care issues including hypercalcemia, management of bone pain, spinal cord compression and treatment options in the context of prostate cancer. 6) Devise and communicate appropriate plans for preventing, monitoring and treating adverse reactions associated with treatment of cancers.

4 Epidemiology of Prostate Cancer New cases: 180,890. Deaths: 26,120. Lifetime risk: 1 in 7 15% will be Dx with prostate cancer Dx: median age 66 years, Death: median age 80 years Incidence & Death: African Americans > Caucasian Americans American Cancer Society: Cancer Facts and Figures Atlanta, Ga: American Cancer Society, Available online.exit Disclaimer Last accessed Feb 24, NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

5 Etiology and Pathogenesis Multifocal adenocarcinomas. Prostatic intraepithelial neoplasia (PIN) is a premalignant lesion that precedes prostate cancer by 10 years or more. Driver: androgen receptor and androgens Testosterone and dihydrotestosterone Semin Oncol 2013; 40(3):

6 Intratumoral androgen synthesis Bypass testosterone and generate DHT from androsterone Bypass pathway: cancer cell Major pathway (CYP17A1; HSD3B1,2; SRD5A1,2) Endocr Relat Cancer 2011; 18(5): 10.

7 Risk Factors Age: <40 yr rare, median Dx 66 yr, death 80 yr Race-ethnicity: American-African (most common), Asian (rare) Family history of prostate cancer: 16% vs 8% (no FH) Occupation: Textile, industrial chemical exposed Obesity: increase risk of aggressive disease American Cander Society. Cancer Facts & Figures Atlanta: American Cancer Society; 2014 SEER Cancer Statistics Factsheets: Prostate Cancer. National Cancer Institute. Bethesda, MD,

8 Screening & Prevention

9 Screening Data controversial Indolent malignancy vs. the harms Over diagnosis and over treatment Method: Periodic PSA + DRE evaluations in asymptomatic men Digital Rectal Exam (DRE) Prostate Specific Antigen (PSA) BMJ 2010;341: c4543, BJU 2011;Int 107 (6):

10 Screening Recommendations *High Risk: African American, Men with 1 st -degree relative diagnosed with prostate cancer at age <65 years. USPSTF: Screening may lead to unnecessary testing and treatment General agreement is that a PSA >4ng/ml should require further workup. However, some would argue a cutoff PSA > 2.5 ng/ml based on the Goteborg study

11 ASCO & AUA: Prevention Asymptomatic men with PSA 3.0 ng/ml who are regularly screened with PSA for early detection of prostate cancer may benefit from dutasteride or finasteride for 7 years for the prevention of prostate cancer and the potential risks. Note: Neither finasteride nor dutasteride is FDA approved for preventing or reducing risk of prostate cancer. The Journal of urology 2009;181(4):

12 Prevention Selenium and Vitamin E The Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (1998) Selenium and Vitamin E Cancer Prevention Trial (SELECT) (2009, 2011) SWOG S9917 (2011) Fleshner NE (2011) DFMO, Soy isoflavones, SERM, cox-2 inhibitors, Vitamin D, green tea catechins, lycopene, in early clinical trials: No recommendation Journal of the National Cancer Institute1998;90(6):440-6., Jama. 2009;301(1):39-51., Jama 2011;306(14): , Cancer prevention research. 2011;4(11): , JCO 2011;29(17):

13 Signs and Symptoms Asymptomatic with early disease Advanced stage disease 1. Alterations in micturition 2. Impotence 3. Lower extremity edema 4. Anemia 5. Weight loss Localized Disease Asymptomatic Locally Invasive Disease Ureteral dysfunction, frequency, hesitancy, and dribbling Impotence Advanced Disease Back pain Cord compression Lower extremity edema Pathologic fractures Anemia Weight loss

14 Natural History of Disease Indolent growth is common in early stages Spreads by local extension, via lymphatics or regional lymph nodes and hematogenously Metastasizes to the bone most commonly (80%) also to the liver and the lung

15 Prognostic factors Extent of tumor Indolent: > 5yr, Locally advanced: 1-3yr Histologic grade of tumor Patient's age and health Prostate-specific antigen (PSA) level N Engl J Med 1991; 324 (4): , N Engl J Med 1994; 330 (4):

16 Diagnosis and staging Physical exam, PSA, DRE, serum chemistries Biopsy of the prostate: Trans-rectal biopsy, transurethral resection of the prostate (TURP) Bone scan, CT(LN met?)/mri (bone met?) Histology: Adenocarcinoma 99% Grading: Gleason grade (grades 2-10)

17 Gleason grade Scores of 1-5 are assigned to the primary and secondary growth patterns and assigned score of 2 evaluations are added together for the Gleason score. Scores of 2-4 are slow-growing, well differentiated tumors, scores of 8-10 are aggressive poorly differentiated tumors The higher the score, the greater the probability of extracapsular spread. ACS 1999.

18 7 th Edition American Joint Committee on Cancer (AJCCS) Staging Systems AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC,

19 Treatment

20 Treatment will depend primarily on the stage and grade, but also takes into consideration the patient s age, general health and preferences

21 Localized Disease (T1a-c, T2a-c, N0M0) Observation Active surveillance (AS) Radiation Therapy (RT) (External Beam (EBRT) or Brachytherapy) Radical Prostatectomy (RP) + Pelvic lymph node dissection (PLND) Androgen Deprivation Therapy (ADT) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

22 Observation Monitors course of disease with PSA and DRE every 6 months. If cancer becomes symptomatic or symptoms are imminent, invention with palliative therapy is warranted. Repeat prostate biopsy not recommended Advantage: avoid immediate morbidity associated with treatment Disadvantage: Risk of complications such as urinary retention or pathologic fracture without symptoms NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

23 Active surveillance (AS) Involves actively monitoring the disease. If cancer is noted to progress - intervention with curative therapy is indicated Monitor PSA, DRE, and repeat prostate biopsies. Treatment is initiated with rising PSA, Increasing Gleason score or tumor volume on biopsy Schedule of monitoring and classification for progression indicating further treatment are yet to be clearly defined. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

24 Active surveillance (AS) Advantages: Avoid immediate morbidity associated with treatment, maintain QOL, avoid unnecessary treatment, decreased initial costs Disadvantages: Risk of progression, chance of missed opportunity for cure, increased anxiety, requires frequent medical exams and periodic biopsies, uncertain long term natural history of prostate cancer, subsequent treatment may be more intense NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

25 External Beam RT or Brachytherapy Appears equivalent to surgery in outcome Option for patients who are not surgical candidates Benefits versus surgery: less bleeding, avoids risks of anesthesia (MI and PE), low risk of urinary incontinence and stricture, short term preservation of erectile function Disadvantages versus surgery: treatment course of 8-9 weeks, 50% have temporary bowel or bladder symptoms during therapy, erectile dysfunction increases over time, radiation proctitis NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

26 External Beam RT Candidates for definitive radiation therapy must have a confirmed pathologic diagnosis of cancer that is clinically confined to the prostate and/or surrounding tissues (stage I, stage II, and stage III). Staging laparotomy and lymph node dissection are not required. Brachytherapy Patients undergoing brachytherapy are often selected for favorable characteristics that include the following: Low Gleason score. Low PSA level. Stage T1 to T2 tumors.

27 Radical Prostatectomy (RP) RP appropriate if tumor is definitive curative therapy Sig perioperative morbidity, so reserved for life expectancy >10 years. A radical prostatectomy is usually reserved for patients who: Are in good health and elect surgical intervention. Have tumor confined to the prostate gland (stage I and stage II). Disturbance of the male integral system following radical prostatectomy: (A) preoperative and (B) postoperative. Sphincteric laxity is due to radical prostatectomy. European urology 2009;55: doi: /j.eururo , J Urol 1990; 143 (3): , J Clin Oncol 1994; 12 (11):

28 Pelvic lymph node dissection (PLND) Indicated if probability of lymph node involvement is >2% Extensive PLND is preferred and includes removal of all lymph node bearing tissue from the area.

29 RP +/- PLND Complication Early mortality (0.3%) Bladder contracture (1-22%) Incontinence (0-17%) Impotence (63% retain potency with bilateral nerve sparing procedure)

30 Androgen Deprivation Therapy (ADT) Goal: to induce castrate levels of testosterone 1) Surgical castration: Bilateral orchiectomy 2) Medical/chemical castration: Luteinizing hormone-releasing hormone (LHRH) agonist or antagonist 3) Goal serum testosterone <50ng/dl 1 month after initiation of therapy NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

31 Orchiectomy (LHRH) LHRH agonist, LHRH antagonist CYP17 inhibitor

32 Androgen Deprivation Therapy (ADT) Combination with RT in low and intermediate risk disease D Amico et al. (JAMA 2004;292(7): ) RTOG Trial (NEJM 2011;365(2): ) No role for adjuvant ADT after prostatectomy in low risk patients. Use after prostatectomy in patients with positive LN has shown mixed results and is discouraged outside of a clinical trial NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

33 Management of Prostate Cancer with High and Very High Recurrence Risk*

34 Treatment of Locally Advanced Disease Stage C (T3 and T4) RT± Neoadjuvant/Adjuvant/Concurrent Hormonal Therapy Radical Prostatectomy with PLND ± Neoadjuvant/Adjuvant/Concurrent Hormonal Therapy NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

35 Treatment of Locally Advanced Disease Stage C (T3 and T4) RT± Neoadjuvant/Adjuvant/Concurrent Hormonal Therapy Multiple studies have evaluated the combination of ADT with RT in patients with high risk disease compared with either therapy alone. Studies have also compared short term ADT to long term ADT in high risk patients A recent meta-analysis of evaluated hormonal therapy after primary therapy of radiation or prostatectomy for men with locally advanced prostate cancer. ADT with RT improved 5 year OS, disease-specific survival, and DFS. No significant difference in overall survival in the prostatectomy groups NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V Cancer treatment reviews. 2009;35(7):

36 Treatment of Locally Advanced Disease Stage C (T3 and T4) RT± Neoadjuvant/Adjuvant/Concurrent Hormonal Therapy Usually starts prior to radiation, continues during radiation and for 2-3 years after radiation. Optimal duration of neoadjuvant therapy for those with high recurrence risk is 2-3 years. Flutamide is FDA-approved for use with LHRH agonist as combination therapy for neoadjuvant hormonal therapy with radiation. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

37 Radical Prostatectomy with PLND ± Neoadjuvant/Adjuvant/Concurrent Hormonal Therapy More than 13 clinical trials with more than 2000 patients enrolled to assess neoadjuvant hormonal therapy (NHT) with LHRH agonists alone or in combination with anti-androgens. Overall, was safe and feasible to administer before prostatectomy, and was associated with a decrease in serum PSA levels, smaller prostate volumes, a decrease in positive surgical margins, decrease in rate of positive lymph node metastasis, and but no difference in biochemical DFS. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

38 Radical Prostatectomy with PLND ± Neoadjuvant/Adjuvant/Concurrent Hormonal Therapy A trial of 481 patients with high-risk prostate cancer after radical prostatectomy received adjuvant ADT for 2 years. This study reported 5 year biochemical failure-free survival of 92.5% and overall survival or 95.9% A meta-analysis of adjuvant hormonal therapy showed for hormonal therapy after prostatectomy, there was no significant OS advantage with ADT Currently, neoadjuvant and adjuvant hormonal therapy are not recommended in combination prostatectomy. Clinical trials are ongoing. Cancer treatment reviews. 2009;35(7): , JCO 2011;29(15):

39 Recurrent or Metastatic Disease

40 Principle of treatment (1) Need to distinguish: PSA recurrence vs. overt metastatic disease. Those with a PSA alone recurrence may not need immediate start of ADT. PSA velocity, toxicity of ADT and patient wishes are taken into consideration with treatment decisions. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

41 Principle of treatment (2) Consider intermittent ADT in this clinical setting. Patients with long PSA doubling time (PSADT) or older age, observation may be appropriate. Those with the following criteria may be considered for initiation of ADT. A. Rapid PSA velocity, short PSADT B. Long life expectancy NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

42 Treatment option 1 st line hormonal therapy A. Bilateral Orchiectomy (removal of the testes) B. Luteinizing hormone-releasing hormone (LHRH) agonists C. LHRH antagonist D. Antiandrogen (AA) E. Combined androgen blockade LHRH + AA F. Intermittent androgen deprivation (IAD) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

43 Treatment option 2 nd line hormonal therapy A. Antiandrogen withdrawal B. Corticosteroids C. Ketoconazole D. Megestrol acetate Metastatic Castration Resistant Prostate Cancer (CRPC) Systemic therapy NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

44 Bilateral Orchiectomy 1) Immediate drop in testosterone levels 2) Previous gold standard 3) Benefits of adding antiandrogens to surgical castration is unclear 4) Side effects: Impotence, hot flashes NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

45 Continuous (-) LHRH agonists The hypothalamus situated in the brain is stimulated to produce pulses of Luteinizing Hormone Releasing Hormone (LHRH) A. This in turn stimulates the pituitary gland to produce Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH). LHRH agonists LHRH antagonists LH travels through the bloodstream to the testicles, B where it joins with cells which secrete testosterone. An enzyme in the prostate then convert s testosterone into a substance called dihydrotestosterone (DHT) which stimulates the growth of prostate cancer cells C. DHT

46 LHRH agonists: Dosage regimen LHRH agonists are a reversible method of androgen ablation and are as effective as orchiectomy in treating prostate cancer. Also referred to as gonadotropin-releasing hormone (GnRH) agonists.

47 LHRH agonists: Outcomes Several RCTs have demonstrated that leuprolide and goserelin are effective agents when used alone in patients with APC. Response rates 80% have been reported, Lower incidence of adverse effects compared with estrogens. No direct comparative trials of the currently available LHRH agonists or the dosage formulations, but a recent meta-analysis reported that there is no difference in efficacy or toxicity between leuprolide and goserelin. Triptorelin is generally considered equivalently effective. Therefore, the choice between the three agents is usually made based on cost and patient and physician preference for a dosing schedule.

48 LHRH agonists: Disease flare-up The disease flare-up with LHRH agonist is thought to be caused by initial induction of LH and FSH by the LHRH agonist and manifests clinically as either increased bone pain or increased urinary symptoms. This flare reaction usually resolves after 2 weeks and has a similar onset and duration pattern for the depot LHRH agonists.

49 Antiandrogen therapy Antiandrogen therapy should precede LHRH agonist and be continued in combination for at least 7 days for patients with overt metastasis to attenuate the tumor flare Adverse events of ADT: Hot flashes, sexual dysfunction, shrinkage of testes and penis, Fatigue, depression, decreased muscle mass, obesity, Insulin resistance, increased lipids.

50 ADT Androgen receptor Erectile dysfunction Hot flashes Increase fat mass Insulin Resistance Decrease muscle mass Osteoporosis Fracture Aromatase Synthesis of Estrogen Estrogen receptor Memory & cognitive loss Hot flashes Lipid changes Bone loss Metabolic syndrome DM, CVD Nutrients 2014, 6(10), ; doi: /nu

51 LHRH agonists: Adverse events LHRH agonist use was associated with increased risk of incident Diabetes (adjusted hazard ratio [HR], 1.44; P <.001), Coronary heart disease (adjusted HR, 1.16; P <.001), Myocardial infarction (adjusted HR, 1.11; P =.03), Sudden cardiac death (adjusted HR, 1.16; P =.004). Men treated with orchiectomy were more likely to develop DM (adjusted HR, 1.34; P <.001) but not CHD, MI, or sudden cardiac death (all P >.20) JCO 2006;24(27):

52 LHRH antagonist: Degarelix An alternative to LHRH agonists: GnRH antagonist MOA: binding reversibly to GnRH receptors on cells in the pituitary gland, reducing the production of testosterone to castrate levels. The major advantage of degarelix over LHRH agonists is The speed at which it can achieve the drop in testosterone levels with no surge of LH or FSH levels; Castrate levels are achieved in 7 days or less with degarelix, compared to 28 days with leuprolide, Eliminating the tumor flare seen and need for antiandrogens

53 LHRH antagonist: Degarelix RCT of 610 men with advanced prostate cancer, degarelix was shown to be equivalent to leuprolide in lowering testosterone levels for up to 1 year and is approved by the FDA for advanced prostate cancer. The most frequently reported adverse reactions Injection sites reactions, including pain (28%), erythema (17%), swelling (6%), induration (4%) and nodule (3%). Elevations in LFT (10%) BJU international. 2008;102(11):

54 LHRH antagonist: Degarelix Degarelix has not been studied in combination with antiandrogens and routine use of the combination cannot be recommended. Currently, degarelix can be considered in 1 st -line setting where flare up from LHRH agonist is a major concern.

55 Antiandrogens: Flutamide, Bicalutamide, Nilutamide Recent meta-analysis determined that monotherapy with antiandrogens is less effective than LHRH agonist therapy. Efficacy of the antiandrogens was similar Flutamide has a response rate of 50-87%, Bicalutamide has a response rate of 54-70%, and Nilutamide has a response rate of approximately 40%

56 Antiandrogens: Flutamide, Bicalutamide, Nilutamide Advanced prostate cancer: All currently available antiandrogens are indicated only in combination with androgen-ablation therapy; Flutamide (combo with LHRH agonist more diarrhea) and Bicalutamide are indicated in combination with an LHRH agonist, and Nilutamide is indicated in combination with orchiectomy. Antiandrogens can reduce the symptoms from the flare phenomenon associated with LHRH agonist therapy.

57 Comparison of the Antiandrogens

58 Combined androgen blockade (CAB) LHRH + AA Up to 80% respond to initial hormonal manipulation, But relapse within 2 to 4 years after initiating therapy Resistance mechanism: 1) The tumor could be heterogeneously composed of cells that are hormone-dependent and hormone-independent, or 2) The tumor could be stimulated by extratesticular androgens that are converted intracellularly to DHT. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

59 CAB LHRH + AA The combination of LHRH agonist with flutamide yields response rates greater than 90% in previously untreated patients but less than 35% have been observed with this combination in patients previously treated with initial hormonal manipulation. Clinical study: Crawford ED, et al. (NEJM 1998;321(7): ) Crawford ED, et al. (J Steroid Biochem 1990;37(6):961-3.) Tyrrell CJ, et al. (European urology 2000;37(2): ) Prostate Cancer Trialists' Collaborative Group. (Lancet 2000;355(9214): ) Samson DJ, et al. (Cancer. 2002;95(2): )

60 CAB LHRH + AA CAB is more ADRs leading to withdrawal from therapy Weigh the costs of combined therapy against potential benefits CAB may be most beneficial for improving survival in patients with minimal disease and for preventing tumor flare, particularly in those with advanced metastatic disease. All other patients may be started on LHRH monotherapy, and an antiandrogen may be added after several months if androgen ablation is incomplete. NCCN s current stance is CAB provides modest to no benefit over ADT alone NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

61 Intermittent androgen deprivation (IAD) With IAD, patients are started on either an LHRH analog alone or on combined androgen blockage. They are monitored and when PSA has returned to a pre-specified baseline (typically 4 ng/dl) androgen suppression is discontinued. PSA is monitored while the patient is off androgen ablation therapy and therapy is re-started at a pre-defined PSA (typically ng/dl). Advantages of IAD include decreased cost and potentially decreased adverse effects. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

62 Intermittent androgen deprivation (IAD) Clinical Study Crook JM, et al. NEJM 2012;367(10): Hussain M, et al. NEJM 2013;368(14): Niraula S, et al. JCO 2013;31(16): Sciarra A, et al. European urology. 2013;64(5): Summary: 1) For men with biochemical failure only, consider IAD as no difference in OS was seen 2) IAD may be considered for men with metastatic disease. Largest trial was deemed inconclusive. 3) Close monitoring and F/U are required, especially during off treatment periods. NCCN CliPractice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

63 Recurrent or Metastatic Disease 2 nd line hormonal therapy May be considered when a tumor is resistant to initial ADT, especially if the PSA doubling time is < 10 months. Corticosteroids, ketoconazole, and megestrol acetate are generally reserved for patients without evidence of distant metastases NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

64 Antiandrogen withdrawal Standard second line therapy 20-30% respond just from androgen withdrawal. Generally short duration of response. Mechanism unknown, but potentially new mutations and androgen receptor changes over time making the tumor cells resistant to AA. Half-life differences between antiandrogens will determine the time to response (6-8 weeks for flutamide) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

65 Corticosteroids Dexamethasone or prednisone Mechanism of action: Suppression of ACTH and subsequently adrenal androgens Dose: Prednisone 5-10mg, Dexamethasone PO mg qd NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

66 Ketoconazole Inhibits androgen synthesis in the testes and the adrenal gland and it has rapid onset of action Dose: PO q 8h, start lower and titrate upward Side effects: N & V (33%) impotence, gynecomastia, dry skin, increased LFTs, and rarely, hepatitis Drug interaction with p450s NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

67 Megestrol acetate Proposed method: Inhibits release of LH, Blockade of androgen receptor, and Inhibition of 5-alpha reductase activity Dose: 40mg Side effects: Fluid retention, mild appetite stimulation NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

68 Metastatic Castration Resistant Prostate Cancer (CRPC)

69 Metastatic Castration Resistant Prostate Cancer (CRPC) CRPC) = serum testosterone <50 ng/dl and disease progression NCCN Recommendations A. Continue ADT and maintain castrate testosterone concentrations B. Consider sipuleucel-t for asymptomatic or minimally symptomatic patients without liver metastases, ECOG 0-1 and greater than 6 month life expectancy C. First line therapy (or following sipuleucel-t therapy if received) options based presence or absence of visceral metastases NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

70 First line therapy 1) No visceral metastases: Enzalutamide (category 1), Abiraterone + prednisone (category 1), Docetaxel + prednisone (category 1), Radium-223 for symptomatic bone metastases (category 1), Clinical trial, Secondary hormonal therapy antiandrogen, antiandrogen withdrawal, ketoconazole, corticosteroids NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

71 First line therapy 2) Visceral metastases: Docetaxel + prednisone (category 1), Enzalutamide (category 1), Abiraterone + prednisone, Alternative chemotherapy (mitoxantrone), Clinical trial NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

72 Subsequent therapy after progression Vis Met Pre E/A Type A D E A+P C+P D+P M R S-T HT BSC CT Vis Met Pre Doce No Met Pre E/A No Met Pre Doce (cat1) (rechallenge) (cat1) (cat1) (cat1) (cat1) (rechallenge) (cat1) (cat1) (cat1) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V (cat1) (cat1) Enzalutamide (E), Abiraterone (A), prednisone (P), Radium-223 if bone predominate (R), Cabazitaxel (C), Sipuleucel-T if asymptomatic or minimally symptomatic (S-T), Clinical trial (CT), Docetaxel rechallenge (D), Alternative chemotherapy (mitoxantrone: M), Other secondary hormonal therapy (HT), Best supportive care (BSC) Other secondary hormonal therapy (antiandrogen, antiandrogen withdrawal, ketoconazole, corticosteroids, DES or other estrogen),

73 JCO 2014;32(30): ASCO/CCO Recommendations

74 Systemic therapy Docetaxel + Prednisone Abiraterone Enzalutamide Mitoxantrone/Prednisone Radium-223 Sipuleucel-T Cabazitaxel NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

75 Docetaxel + Prednisone TAX 327: Over 1000 patients with metastatic CRPC were randomized to 1 of 2 regimens of docetaxel/prednisone or mitoxantrone/prednisone. The initial and updated follow up showed a significant improvement in median survival for patients receiving docetaxel q3 weeks/prednisone compared to mitoxantrone prednisone JCO 2008;26(2): , NEJM 2004;351(15):

76 Overall survival in the TAX 327 study JCO 2008;26(2):

77 TAX 327 JCO 2008;26(2): , NEJM 2004;351(15):

78 Docetaxel + estramustine SWOG 9916: Over 600 patients with metastatic CRPC were randomized to docetaxel/estramustine or mitoxantrone/prednisone. A significant improvement in median survival was seen with the docetaxel group (17.5 months vs months, p<0.05). Patients receiving estramustine had significantly higher incidences of severe neutropenic fever, N/V, and cardiovascular events requiring anticoagulation. Due to higher toxicity, docetaxel/estramustine not routinely used NEJM 2004;351(15):

79 SWOG 9916: Overall survival HR = 0.80 (95% CI, ) NEJM 2004;351(15):

80 Docetaxel + Prednisone Studies of combining bevacizumab or lenalidomide with docetaxel/prednisone have failed to improve OS and suggested increased toxicity Docetaxel/prednisone benefit seen in patients with and without symptoms. Per NCCN, may be considered for rapid progression or visceral metastases despite lack of symptoms. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

81 Abiraterone + Prednisone Abiraterone is a first in class selective inhibitor of androgen biosynthesis that blocks cytochrome P450 CYP17, a critical enzyme in testosterone biosynthesis Dosing: Abiraterone 1000 mg daily + prednisone 5 mg twice daily. PK: Food can increase abiraterone absorption, therefore it should be taken on empty stomach 1 hour before or 2 hours after meal. Prednisone helps obstruct the activation of cortisol deficit induced negative feedback mechanism. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

82 COU-AA-302: 2015 Report This final analysis of the COU-AA-302 trial demonstrates that abiraterone acetate plus prednisone prolongs overall survival compared with placebo plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. At this final analysis, the safety profile of abiraterone acetate plus prednisone was consistent with that reported at previous interim analyses. Lancet Oncol 2015; 16:

83 Abiraterone: Toxicity Fatigue, arthralgia, peripheral edema, hepatotoxicity, diarrhea, hypophosphatemia, hot flushes, urinary tract infections, AF. Mineralocorticoid-related effects were more common in the abiraterone-prednisone group: HTN, hypokalemia, and edema. Most were grade 1 or 2 adverse events (mild-moderate). Monitor transaminases, blood pressure, and potassium. Avoid spironolactone. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

84 Enzalutamide (Androgen receptor inhibitor) MOA: blocks androgen binding and subsequent translocation of the receptor to the nucleus and its attachment to DNA. higher potency for androgen receptor than traditional antiandrogens A major metabolite of the enzalutamide, N-, exhibits activity similar parent cpd. Dosing: 160mg orally once daily. PK: May be taken with or without food. Capsules should be swallowed whole and not chewed, dissolved, or opened NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

85 Figure 1. Radiographic PFS and OS. Figure 2. Times until the Initiation of CMT and an Increased Level of PSA. PREVAIL trial enzalutamide 160mg po daily or placebo. N Engl J Med 2014; 371:

86 AFFIRM Trial NEJM 2012;367(13):

87 Enzalutamide: Toxicities Fatigue, back pain, diarrhea, headache, constipation, arthralgia, hot flushes, hypertension. Seizures are rare but reported. Falls including fall related injuries were more common in enzalutamide patients. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

88 Enzalutamide: PK issue Strong CYP3A4 inducer, a moderate CYP2C9 & CYP2C19 inducer. It is metabolized by CYP2C8 and CYP3A4, with CYP2C8 primarily responsible for formation of active metabolite. Concomitant use of strong CYP2C8 should be avoided. Enzalutamide may decrease concentration of drugs that are substrates for CYP 3A4, 2C9 or 2C19 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

89 Mitoxantrone/Prednisone N=161, mitoxantrone 12 mg/m 2 IV x 1 + prednisone bid vs. prednisone alone. Generally only considered for symptomatic patients who cannot tolerate docetaxel M+P NS P Duration of JCO 1996;14(6):

90 Radium-223 For patients with symptomatic bone only disease Radium-223 is an alpha-emitting radiopharmaceutical that selectively binds to areas of bone metastases. NCCN category 1 for patients with symptomatic bone metastases and no known visceral metastases prior to and after docetaxel therapy NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V DOI

91 Radium-223: ALSYMPCA Trial Random to 6 injections of radium-223 given 1 injection q 4 wks or placebo The median OS was 14 months compared with 11.2 months in placebo group (P = ). Median time to first SREs was 15.6 mo vs. 9.8 mo (p<0.001). NEJM 2013;369(3): Sign improvement in QOL by FACT-P score with radium 223. Grade 3 or 4 toxicities: anemia 11%, neutropenia 2%, and thrombocytopenia 4%

92 Sipuleucel-T For asymptomatic or minimally symptomatic patients Sipuleucel-T is an active cellular immunotherapy, a type of therapeutic vaccine consisting of autologous peripheral-blood mononuclear cells. Dosing: Each dose contains > 50 million autologous CD54+ cells, obtained through leukophoresis, activated with PAP-GM-CSF. It is administered to patient every two weeks for total of 3 doses. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

93 Sipuleucel-T: IMPACT Trial Metastatic CRPC who were asymptomatic or minimally symptomatic. Inclusion: > 6 month life expectancy and PSA > 5 ng/ml. Exclusion: ECOG >2, visceral metastases or had received other treatment within 28 days. 341 patients received sipuleucel-t and 171 placebo. NEJM 2010;363(5):

94 Sipuleucel-T: IMPACT Trial There was a 22% RRR of death (HR 0.78; 95% CI, ). Median OS was 25.8 months in patients receiving sipuleucel-t compared with 21.7 months in patients receiving placebo (P=0.03). Median time to disease progression was not significantly different between the 2 groups (14.6 weeks v 14.4 weeks, p=0.63). Common Aes: chills, pyrexia and headache NEJM 2010;363(5):

95 Sipuleucel-T: IMPACT Trial Sipuleucel-T should be considered for patients with metastatic CRPC and has following: 1. No or minimal symptoms; 2. Good performance status; 3. > 6 months life expectancy; 4. No visceral disease. NCCN category 1 recommendation NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

96 Cabazitaxel It is a taxane derivative which binds to tubulin promoting assembly into microtubules & inhibiting disassembly by which stabilizing microtubules. This inhibits microtubules depolymerization. Dosing: 25 mg/m 2 IV every 3 weeks with prednisone. It is important to pre-medicate patient with an antihistamine, a corticosteroid, and a H-2 antagonist. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

97 TROPIC Trial: OS Lancet. 2010;376(9747):

98 Cabazitaxel: TROPIC Trial Higher incidences of severe neutropenia, diarrhea and FN (8%) in the cabazitaxel arm. Another side effect of concern is the 30-day mortality within last dose of drug of 4.9% in cabazitaxel group compared with 2% in mitoxantrone. It is more likely higher incidences of neutropenia and diarrhea Lancet. 2010;376(9747):

99 Cabazitaxel NCCN category 1 recommendation after progression on docetaxel regimens. However, due to significant toxicities, caution should be used in patient selection. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

100 Sequencing of agents in castration-resistant prostate cancer Lancet Oncology 2015; 16: e279 92

101 Supportive Care

102 Supportive Care Hypercalcemia Osteoporosis Diabetes and heart disease Bone metastasis and bone pain Spinal cord compression (SCC)

103 Hypercalcemia Pathophysiology Humoral factors secreted: PTHrP; non-pthrp related factors Substantial bone turnover from extensive metastatic disease Absorptive hypercalcemia from excessive vitamin D activation by the tumor Treatment options IV fluid +/- diuretics Bisphosphonates Calcitonin Gallium nitrate Hemodialysis Denosumab CJASN. 2012;7(10):

104 Hypercalcemia: IV fluid +/- diuretics NSS at ml/hr with goal urine output of >75 ml/hr. Loop diuretics: Decrease calcium reabsorption, increasing urine excretion. However, little data to show significant lower serum calcium levels. Therefore, loop diuretics may be used to manage fluid overload during aggressive hydration CJASN. 2012;7(10):

105 Bisphosphonate: Dosage regimen The American journal of medicine. 1993;95(3): , JCO 2001;19(2):

106 Hypercalcemia: Calcitonin A peptide hormone released by the thyroid gland that increases urinary calcium excretion and inhibits bone resorption by osteoclasts. Rapid onset (2-6 hours) but tachyphylaxis occurs limiting duration of Tx. Generally used in combination with IV fluid and bisphosphonates in severe, symptomatic hypercalcemia to decrease the serum calcium level quickly. Doses of 4-8 units/kg IM or SQ are used every 6-12 hours. Lancet. 2010;376(9747):

107 Hypercalcemia: Gallium nitrate Thought to work by reducing osteoclast activity and bone remodeling and is administered as a 5 day continuous infusion (200mg/m2/day). It has more toxicity than other therapies, including renal impairment, lethargy, altered mental status, nausea, vomiting.

108 Hypercalcemia: Hemodialysis Indicated for patients with acute hypercalcemia and acute renal failure, especially in patients with oliguria making hydration problematic.

109 Hypercalcemia: Denosumab A monoclonal antibody that binds receptor activator of nuclear factor kappa B ligand (RANKL) thereby inhibiting osteoclast function. Currently approved to prevent SREs in patients with cancer. One of the most common toxicities is hypocalcemia. Journal of the National Cancer Institute. 2013;105(18):

110 Osteoporosis ADT increases the risk for osteoporosis and is associated with a 21%-54% increase in fracture risk. Screening and treatment based on normal population. Calcium 1200mg daily and vitamin D IU daily are recommended for all men over the age of 50 years. Additional treatment indicated if 10-year probability of hip fracture is > 3% or major osteoporosis related fracture > 20% NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

111 Osteoporosis: Recommendation Patients with a fracture risk that warrants drug therapy include: Zoledronic acid 5mg IV annually, Alendronate 70mg PO weekly, or Denosumab 60 mg SQ every 6 months NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

112 Diabetes and Heart disease ADT therapy causes physiologic effects such as increased fat mass, decreased lean muscle mass, increased cholesterol and triglycerides, and decreased insulin sensitivity. These events have been linked to DM and CVD A study 73,196 patients with locoregional prostate cancer found that use of ADT was associated in an increased risk of DM (HR 1.44;p<0.001), CAD (HR 1.16; p<0.001), MI (HR 1.11; p=0.03) and sudden cardiac death (HR 1.16; p=0.004). Usual population screening and interventions for DM and heart disease are recommended at this time NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V , JCO 2006;24(27):

113 Bone metastasis and bone pain Prostate cancer most commonly metastasizes to the bones. ADT may result in bone loss that increases the risk of complications from bone metastases. Prevention of complications from bone metastases important. SRE include pathologic fractures (vertebral or nonvertebral), SCC, Sx to bone, RT to bone, or change CMT to treat bone pain. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

114 Bone metastasis: Bisphosphonate Zoledronic acid is recommended to prevent SREs in prostate cancer. Metastatic CRPC pt. zoledronic acid 4mg every 3-4 weeks can be given. Overall duration of treatment is unknown. Pamidronate has not been shown to be efficacious compared with placebo in patients with metastatic CRPC. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

115 Bone metastasis: RANKL inhibitor RCT of men with CRPC and bone metastases randomized 1904 patients to denosumab 120mg SQ or zoledronic acid 4mg IV every 4 weeks. Median time to first SRE was 20.7 months for denosumab vs 17.1 months for zoledronic acid (p=0.0002). There were significantly more grade 3 or 4 AEs in the denosumab group. Hypocalcemia was seen in 13% of denosumab patients vs 6% of zoledronic acid An increased risk of hypocalcemia at CrCL of < 60 ml/min has been noted. ONJ was seen in 2% of the denosumab group and 1% of zoledronic acid group Lancet. 2011;377(9768):

116 Bone metastasis: RANKL inhibitor Denosumab has been evaluated in patients with non-metastatic CRPC at high risk for bone metastasis. Patients at high risk for bone metastasis were characterized by PSA of 8 ng/ml within 3 months of randomization or higher or PSA doubling time of 10 months or less or both. Over 1400 patients were randomized to receive denosumab 120mg SQ every 4 weeks or placebo until the incidence of bone metastasis. Denosumab increased the bone metastasis free survival by 4.2 months (median 29.5 vs months; HR 0.85, CI ). No difference in OS was noted. Significant AEs included ONJ in 5% and hypocalcemia in 2% of patients receiving denosumab. Journal of the National Cancer Institute. 2004;96(11):

117 Bone metastasis: RANKL inhibitor Clinical trials are ongoing to evaluate zoledronic and denosumab in patients receiving ADT for prostate cancer & bone metastasis Patients receiving zoledronic acid or denosumab should be monitored for the development of ONJ. Most cases have occurred after invasive dental procedures. Dental work completed prior to initiation of therapy. Patients should also receive calcium and vitamin D due to the risk of hypocalcemia NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V

118 Bone metastasis: Radiation Therapy Strontium 89 and samarium-153 External beam radiation Beta-emitting radiopharmaceuticals used to palliate pain from bone metastases. Radionuclides which concentrate in osteoblastic bone lesions and delivers local RT to site of uptake % analgesic response rates, median duration 3-6 months Major dose limiting toxicity is myelosuppression due to BM suppression by the beta particle penetration. Palliative radiation can increase the risk of BM suppression and prevent patients from receiving future systemic CMT. Used to control pain and prevent impending fractures from individual lesions. Pain relief seen in greater than 90% of patients Local control rates range from 75-90% European urology. 2013;63(2):

119 Spinal cord compression (SCC) Complication of advanced cancer leading to progressive pain, paralysis, sensory loss and sphincter dysfunction if not treated. Considered an oncologic emergency as rapid recognition and treatment are essential for optimal outcomes. Occurs in approximately 2.5% of all cancer patients. Lesions are most common in the thoracic spine (60%), followed by lumbosacral (30%) and cervical (10%). Neurocritical care. 2012;17 Suppl 1:S

120 Spinal cord compression: Steroid Little quality data, but most recommend initiation of corticosteroids if there are no contraindications. Several small studies have evaluated high dose dexamethasone (96-100mg) vs low dose (16mg) or no dexamethasone. Although one study has shown benefit of high dose steroids prior to radiation, high doses are associated with more toxicity. Current recommendations include dexamethasone 8-10mg initially followed by 16mg/day in divided doses. High doses may be considered in patients with significant paraparesis. Neurocritical care. 2012;17 Suppl 1:S , International journal of radiation oncology, biology, physics. 2012;84(2):

121 Spinal cord compression: Sx & RT A meta-analysis evaluated RT vs. surgery for patients with malignant SCC. It found surgical patients were more likely to recover ambulation and have pain control compared to RT. Surgery is associated with complications. Therefore surgery is recommended for patients with a good prognosis with a single area of compression. Radiation recommended for patients who are not candidates for surgical decompression. International journal of radiation oncology, biology, physics. 2012;84(2):

122 Suthan Chanthawong B. Pharm, BCP, BCOP Faculty of Pharmaceutical Sciences, Khon Kaen University