Optimal integration of new treatments for castration resistant prostate cancer

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Optimal Integration of New Treatments for Castration-Resistant Prostate Cancer Dr. Sankar Srinivasan, AB, FACP Consultant Oncologist, Apollo Hospitals

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  • The consensus was that HRPC is a state where there may be some androgen sensitive cells, but where androgen independent cells dominate. The androgen receptor has undergone a conformational change and antiandrogens may impose agonist activity. The androgen receptor gene may be over expressed or the androgen receptor maybe more sensitive to low levels of oestrogen. The practical definition is a consecutive series of increasing PSA levels after a nadir is reached with HT. Patients must have had a trial of anti-androgen withdrawal and have castrate levels of testosterone. The majority of the group agreed that in HRPC you should continue with castration therapy, because there will be a proportion of cells that are androgen sensitive. Furthermore, withdrawing castration therapy may increase bone pain and the growth of the tumour. It was agreed that the biology of HRPC is different to that 20 years ago. Patients are being presented at an earlier stage of disease and fewer patients are presenting with symptomatic metastatic prostate cancer. In the USA, HRPC is used to refer to patients who have failed local therapies.
  • AR, androgen receptor.
  • PSA, prostate-specific antigen.
  • BID, twice daily; ECOG, Eastern Cooperative Oncology Group; mCRPC, metastatic castration-resistant prostate cancer; PS, performance status.
  • AA, abiraterone acetate; CI, confidence interval; HR, hazard ratio; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival.
  • CI, confidence interval; HR, hazard ratio; PSA, prostate-specific antigen; rPFS, radiographic progression-free survival.
  • LFT, liver function test.
  • AR, androgen receptor; CRPC, castration-resistance prostate cancer; PC, prostate cancer; PK, pharmacokinetics.
  • NYR, not yet reached; PCCTWG, Prostate Cancer Clinical Trials Working Group; PSA, prostate-specific antigen.
  • CRPC, castration-resistant prostate cancer; HR, hazard ratio; OS, overall survival.
  • CRPC, castration-resistant prostate cancer; OS, overall survival.
  • CRPC, castration-resistant prostate cancer.
  • CRPC, castration-resistant prostate cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; OS, overall survival; PFS, progression-free survival; PO, orally.
  • CBC, complete blood count; ECOG PS, Eastern Cooperative Oncology Group performance status; mCRPC, metastatic castration-resistant prostate cancer; PSA, prostate-specific antigen; RECIST, response evaluation criteria in solid tumors.
  • CBZP, cabazitaxel, prednisone; CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; MP, mitoxantrone, prednisone; OS, overall survival. TROPIC slide deck. Slide5
  • TROPIC slide deck. Slide34
  • GM-CSF, granulocyte macrophage-colony stimulating factor.
  • MHC, major histocompability complex; TCR, T-cell receptor.
  • CRPC, castration-resistant prostate cancer; IHC, immunohistochemistry; OS, overall survival; PAP, prostatic acid phosphatase; TTP, time to progression. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med . 2004;351:1502-1512.
  • PSA, prostate-specific antigen.
  • CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; OS, overall survival.
  • TTP, time to progression.
  • PSA, prostate-specific antigen.
  • CI, confidence interval; HR, hazard ratio; OS, overall survival; rF-PSA, recombinant fowlpox prostate-specific antigen; rV-PSA, recombinant vaccinia prostate-specific antigen.
  • CRPC, castration-resistant prostate cancer; GM-CSF, granulocyte macrophage-colony stimulating factor; OS, overall survival.
  • CRPC, castration-resistant prostate cancer; HR, hazard ratio; OS, overall survival.
  • Optimal integration of new treatments for castration resistant prostate cancer

    1. 1. Optimal Integration of New Treatments forCastration-Resistant Prostate CancerDr. Sankar Srinivasan, AB, FACPConsultant Oncologist, Apollo HospitalsVisiting Consultant, Ironwood Cancer and ResearchCenter, Phoenix, AZ, USA
    2. 2. Std Hormonal treatments Orchiectomy or Zoladex or Lupron Bicalutamide added for combined hormonal blockade
    3. 3. Case-1  57-yr-old man – T3a PCa, Gleason 4+4 = 8, PSA = 8.2 ng/mL  Undergoes radical prostatectomy  Develops PSA recurrence none in prostatic bed  Started on leuprolide + bicalutamide, and responds for 18 months  Then develops rising PSA, despite bicalutamide withdrawal  PSAs: 4.2 → 5.6 → 7.2 ng/mL  Testosterone: 28 ng/dL  Bone scan and CT scan: Negative for metastatic disease•PSADT = prostate-specific antigen doubling time; CT = computed tomography.•NCCN, 2011.
    4. 4.  Does this patient meet criteria for CRPC? How would you manage this patient?
    5. 5. •HRPC DefinitionPractical definition: a consecutive series of increasing PSA levels after a nadir is reached with HT. Must have had a trial of anti-androgen withdrawal and must have castrate levels of testosterone• Men with HRPC are not treated to cure their disease but simply to improve their quality of life.• The lack of effective treatments for HRPC leads patients to turn to unproven therapies.
    6. 6. Overview Modern approaches to targeting  Autologous cellular androgens immunotherapy: understanding a new paradigm – COU-AA-301 phase III study: abiraterone – IMPACT phase III study: sipuleucel-T – Other androgen-targeted agents: MDV3100 – TBC-PRO-002 phase II study: ProstVac-VF The evolving role of chemotherapy – TAX 327 study: weekly vs 3- weekly docetaxel vs mitoxantrone – TROPIC phase III study: second- line cabazitaxel
    7. 7. Modern Approaches to Targeting Androgens
    8. 8. Androgen Receptor Addiction Is a Hard Habit to Break  Hormonal treatments continue to have antitumor activity  High levels of intratumoral androgens despite castration – Preclinical and clinical evidence of intracrine synthesis  Castration resistance associated with – AR amplification (increased gene dose) – AR mutations that increase AR (transcriptional) activity – ↑ AR (< 2x) expression (ligand driven) in isogenic resistant lines  Identification of oncogenic translocations/fusions driven by androgens + estrogen-response elements (ETS genes; TMPRSS2/ERG in 50% to 70% of prostate cancer)Attard G, et al. Cancer Cell. 2009;16:458-462.
    9. 9. Abiraterone Acetate: Androgen Biosynthesis Inhibitor  Androgens produced at 3 critical sites lead to tumor proliferation – Testes – Adrenal gland – Prostate tumor cells  Abiraterone inhibits biosynthesis of androgens that stimulate tumor cell growth  PSA and radiographic responses in phase I/II studies – Chemotherapy-naive and postchemotherapy patients[1-5]1. Attard G, et al. J Clin Oncol. 2008;26:4563-4571. 2. Attard G, et al. J Clin Oncol. 2009;27:3742-3748.3. Reid AH, et al. J Clin Oncol. 2010;28:1489-1495. 4. Ryan C, et al. J Clin Oncol. 2010;28:1481-1488.5. Danila D, et al. J Clin Oncol. 2010;28:1496-1501.
    10. 10. COU-AA-301: Phase III Study of AbirateroneAcetate in mCRPC Randomized 2:1 Abiraterone acetate 1000 mg/day + Patients with mCRPC Prednisone 5 mg BID progressing after 1-2 (n = 797) chemotherapy Stratified by ECOG PS, worst pain regimens, over previous 24 hrs, previous 1 of which contained chemotherapy, type of progression docetaxel Placebo + (N = 1195) Prednisone 5 mg BID (n = 398)de Bono J, et al. N Engl J Med. 2011;364:1995-2005.
    11. 11. COU-AA-301: Abiraterone Acetate Improves OS in mCRPC 100 HR: 0.646 (95% CI: 0.54-0.77; P < .0001) 80 Abiraterone acetate Median OS: 14.8 mos Survival (%) 60 (95% CI: 14.1-15.4) 40 Placebo Median OS: 10.9 mos 20 (95% CI: 10.2-12.0) Median OS with 2 prior chemo: Median OS with 1 prior chemo 14.0 mos AA vs 10.3 mos placebo 15.4 mos AA vs 11.5 mos placebo 0 0 3 6 9 12 15 18 21 Months AA 797 736 657 520 282 68 2 0de Bono J, et al. N Engl J Med. 355 Placebo 398 2011;364:1995-2005. 306 210 105 30 3 0Copyright © 2011 Massachusetts Medical Society. All rights reserved.
    12. 12. COU-AA-301: All Secondary Endpoints Achieved Statistical Significance Endpoint Characteristic Abiraterone Placebo HR P Value (n = 797) (n = 398) (95% CI) Time to PSA 10.2 6.6 0.58 < .0001 progression, mos (0.46-0.73) rPFS, mos 5.6 3.6 0.67 < .0001 (0.59-0.78) PSA response rate, %  Total 38.0 10.1 < .0001  Confirmed 29.1 5.5 < .0001de Bono J, et al. N Engl J Med. 2011;364:1995-2005.Copyright © 2011 Massachusetts Medical Society. All rights reserved.
    13. 13. COU-AA-301: Adverse Events of SpecialInterest Abiraterone PlaceboAdverse Event, % (n = 791) (n = 394) All Grades Grades 3/4 All Grades Grades 3/4Fluid retention 30.5 2.3 22.3 1.0Hypokalemia 17.1 3.8 8.4 0.8LFT abnormalities 10.4 3.5 8.1 3.0Hypertension 9.7 1.3 7.9 0.3Cardiac disorders 13.3 4.1 10.4 2.3de Bono J, et al. N Engl J Med. 2011;364:1995-2005.
    14. 14. MDV3100: Phase I/II Study in Advanced Prostate Cancer[1]  MDV3100: novel, oral AR antagonist – Blocks testosterone binding to AR, Testosterone synthesis impedes movement of AR to Tumor death nucleus, inhibits DNA binding Testosterone T T – Slows tumor growth and X MDV3100 causes cell death in cancers DNA binding and AR 1 AR binding resistant to bicalutamide 3 activation blocked blocked X X 2 Nuclear  Phase I/II trial conducted to Cell nucleus translocation determine safety, PK, and No prednisone impaired antitumor activity of MDV3100[2] required – Cohorts treated with – N = 140 patients with progressive sequentially escalating doses CRPC, pre- or postchemotherapy of MDV3100 (30-600 mg/day)1. Higano CS, et al. ASCO GU 2011. Abstract 134. 2. Scher HI, et al. Lancet. 2010;375:1437-1446.
    15. 15. Long-term Follow-up of MDV3100: Antitumor Activity  MDV3100 antitumor activity durable both before and after chemotherapy Outcome Chemotherapy Post Naïve Chemotherapy (n = 65) (n = 75) ≥ 50% PSA decline from baseline, % 62 51 Median time to PSA progression, days Per protocol* NYR 316 PCCTWG 2 criteria† 281 148 Median time to radiographic progression, days increase in PSA from baseline with increase ≥ 5 ng/mL 392 175 *≥ 25% † ≥ 25% increase in PSA from nadir with increase ≥ 2 ng/mLHigano CS, et al. ASCO GU 2011. Abstract 134.
    16. 16. Conclusion: Targeting Androgens Advanced prostate cancer is neither hormone refractory nor androgen independent and remains nuclear steroid receptor driven – Hormone therapy works after chemotherapy CYP17 blockade does not cause adrenal insufficiency Multiple lines of treatment available for advanced prostate cancer – Sipuleucel-T, docetaxel, abiraterone, cabazitaxel – The optimal sequence of administration now needs to be defined
    17. 17. Evolving Role of Chemotherapy in theManagement of Castration-Resistant Metastatic Prostate Cancer
    18. 18. TAX 327: Weekly vs 3-Weekly Docetaxel vs Mitoxantrone in CRPC—OS 1.0 Docetaxel 3-weekly Docetaxel weekly Mitoxantrone 0.8 Proportion Alive 0.6 0.4 0.2 0Berthold DR, et al.0 Clin Oncol. 2008;26:242-245. J 1 2 3 4 5 6 7Reprinted with permission. © 2008 American Society of Clinical Oncology. Allrights reserved. Time (years)
    19. 19. Docetaxel-Based Therapy in CRPC:Observations From Long-term Follow-up After 5 yrs of follow-up, 867 deaths (86% of 1006 patients) have occurred Median OS difference between every-3-wk docetaxel and mitoxantrone groups remains highly significant (P = .004)Outcome Every-3-Wk Weekly Mitoxantrone/ Docetaxel/ Docetaxel/ Prednisone Prednisone Prednisone (n = 337) (n = 335) (n = 334)Median OS, mos 18.9 17.4 16.53-yr OS, % 18.6 16.8 13.5Berthold DR, et al. J Clin Oncol. 2008;26:242-245.
    20. 20. Cabazitaxel: A Novel Tubulin-Targeting Agent Selected to overcome the emergence of taxane resistance Preclinical data – Potency equivalent to docetaxel against sensitive cell lines and tumor models – Evidence of activity against tumor cells/models resistant to currently available taxanes Early clinical data from phase I studies demonstrated: – Dose-limiting toxicity: neutropenia – Activity in patients with metastatic CRPC – Moved from phase I to phase III development in a series of trials in a variety of epithelial neoplasmsPivot X, et al. Ann Oncol. 2008;19:1547-1552.Mita AC, et al. Clin Can Res. 2009;15:723
    21. 21. TROPIC: Phase III Registration Trial of Second-line Cabazitaxel in CRPC Stratified by ECOG PS (0,1 vs 2) and measurable vs nonmeasurable disease Mitoxantrone 12 mg/m2 IV q3w + Prednisone 10 mg/day PO for 10 courses Patients with (n = 377) metastatic CRPC progressing on docetaxel Cabazitaxel 25 mg/m2 IV q3w + Prednisone 10 mg/day PO for 10 courses (N = 755) (n = 378)  Primary endpoint: OS  Secondary endpoints: PFS, response rate, safetyde Bono JS, et al. Lancet. 2010;376:1147-1154 .
    22. 22. TROPIC: Main Eligibility Criteria  mCRPC patients with documented disease progression – Measurable by RECIST or – Nonmeasurable: documented rising PSA levels (≥ 2 consecutive rises in PSA over a reference value taken at least 1 week apart) or appearance of new lesion  Previous treatment with a docetaxel-containing regimen  No previous treatment with mitoxantrone  ECOG PS: 0-2  Normal organ function (CBC and serum chemistries)de Bono JS, et al. Lancet. 2010;376:1147-1154 .
    23. 23. TROPIC: Preprotocol Treatment Previous Treatment Mitoxantrone/Prednisone Cabazitaxel/Prednisone (n = 377) (n = 378) Chemotherapy, n (%)  1 regimen 268 (71) 260 (69)  2 regimens 79 (21) 94 (25)  ≥ 3 regimens 30 (8) 24 (6) Docetaxel, n (%)  1 regimen 327 (87) 316 (84)  2 regimens 43 (11) 53 (14)  ≥ 3 regimens 7 (2) 9 (2) Median total previous 529.2 576.6 docetaxel dose, mg/m2 (range) (380.9-787.2) (408.4-761.2) Median time from last 0.70 docetaxel dose to progression, (0-2.9) 0.80 mos (range) (0-3.1)de Bono JS, et al. Lancet. 2010;376:1147-1154 .
    24. 24. TROPIC: OS (Updated ITT Analysis)Survival MP CBZPMedian OS, mos 12.7 15.1HR 0.7295% CI 0.61-0.84P value < .0001 Combined median follow-up: 13.7 mosde Bono JS, et al. ASCO 2010. Abstract 4508. de Bono JS, et al. Lancet. 2010;376:1147-1154.
    25. 25. TROPIC: Treatment-Emergent Grade 3/4 Adverse Events Treatment-Emergent Grade 3/4 Mitoxantrone/ Cabazitaxel/ Adverse Events,* % Prednisone Prednisone (n = 371) (n = 371) Any adverse event 39.4 57.4  Febrile neutropenia 1.3 7.5  Diarrhea 0.3 6.2  Fatigue 3.0 4.9  Back pain 3.0 3.8*Sorted by ≥ 2% incidence rate for grade ≥ 3 events in the cabazitaxel arm.de Bono JS, et al. ASCO 2010. Abstract 4508 .
    26. 26. Cabazitaxel: Evolving Clinical Issues Following FDA approval, the first wave of patients treated were more heavily pretreated than would be expected over time – Effect of dose/toxicity Many important questions remain undefined – Optimal dose – Growth factors? – Cabazitaxel vs docetaxel retreatment – Upcoming clinical trials
    27. 27. Ongoing Cabazitaxel Clinical Trials:Phase III PROSELICA Study Cabazitaxel 20 mg/m² vs 25 mg/m² for the treatment of patients with metastatic castration-resistant prostate cancer and prior treatment with docetaxel – Both doses administered with prednisone Primary objective: overall survivalClinicalTrials.gov. NCT01308580.
    28. 28. Ongoing Cabazitaxel Clinical Trials: Phase III FIRSTANA Study  Cabazitaxel vs docetaxel for the treatment of patients with metastatic castration-resistant prostate cancer and no prior chemotherapy – Cabazitaxel 25 mg/m2 and 20 mg/m2 evaluated – Cabazitaxel and docetaxel both given with prednisone  Primary objective: overall survivalClinicalTrials.gov. NCT01308567.
    29. 29. Autologous Cellular Immunotherapy: Understanding a New Paradigm •
    30. 30. Active Cellular Immunotherapy(Sipuleucel-T) Patient’s white blood cells harvested Short-term culture with protein “cassette” GM-CSF Prostatic acid phosphatase (PAP) Shipping Cells infused back into patient (IV)
    31. 31. Immunotherapy for Prostate Cancer: Mechanism(s) of Action CD4+ T cell Activated TCR dendritic cell Class II MHC Cytokine s TCRTumor antigen Antibodies: circulate in sera Class I MHC bind to tumor cells CD8 T cell Activated CD8+ T cells: traffic to tumor, lyse tumor cells
    32. 32. IMPACT: Phase III Study Physician’s P discretion, Patients with R Placebo including metastatic, asymptomatic or q2w x 3 O phase II G open-label minimally R sipuleucel-T* symptomatic CRPC, 2:1 study no visceral E metastases S Sipuleucel-T S Physician’s (N = 512) q2w x 3 I discretion O N  Primary endpoint: OS  Secondary endpoint: TTP *Prepared using cryopreserved peripheral blood lymphocytesKantoff PW, et al. N Engl J Med. 2010;363:411-422.
    33. 33. IMPACT: Baseline Characteristics Key Inclusion Criteria – Metastatic and castrate resistant – Asymptomatic or minimally symptomatic – Prior chemotherapy permitted Selected Patient Characteristics – Median age: 71 – Median PSA: 50 ng/mL – Hemoglobin: 12.8 g/dL – Bone-only disease: 50% – Bone and soft-tissue disease: 44%Kantoff PW, et al. N Engl J Med. 2010;363:411-422. •
    34. 34. IMPACT Study: OS (ITT Population) P = .032 (Cox model) 100 HR: 0.775 (95% CI: 0.614-0.979) Median survival benefit: 4.1 mos Patients Remaining 75 Alive (%) 50 Sipuleucel-T (n = 341) Median survival: 25.8 mos 25 Placebo (n = 171) Median survival: 21.7 mos 0 0 6 12 18 24 30 36 42 48 54 60 66 Survival (Mos)Kantoff PW, et al. N Engl J Med. 2010;363:411-422.Copyright © 2010. Massachusetts Medical Society. All rights reserved.
    35. 35. IMPACT: Results  Clinical Outcomes – TTP not significantly different between arms – 1 objective response (in active treatment group) – Extensive subgroup analyses were inconclusive Adverse Event, % Sipuleucel-T Placebo Chills 54 13 Pyrexia 29 14 Headache 16 5Kantoff PW, et al. N Engl J Med. 2010;363:411-422.
    36. 36. Another Cancer Vaccine Approach:ProstVac-VF Costimulatory Molecules PSA LFA ICAM- B7-1 Target -3 1 antigen Vaccinia virus Fowlpox virus Plasmid DNA Packaging cell line rV-PSA-TRICOM rF-PSA-TRICOM Vaccine
    37. 37. TBC-PRO-002: Phase II ProstVac-VF Study —OS HR: 0.56 (95% CI: 0.37-0.85) 100 n Deaths Median OS, mo Control 40 37 16.6 80 ProstVac-VF 82 65 25.1 rV-PSA -> 60 rF-PSA OS (%) 40 20 0 0 12 24 36 48 60 MosKantoff PW, et al. J Clin Oncol. 2010;28:1099-1105.Reprinted with permission. © 2008 American Society of Clinical Oncology. All rightsreserved.
    38. 38. Prospect Phase III Trial: ProstVac ± GM-CSF in Metastatic CRPC ProstVac-VF + Patients with TRICOM + low-dose asymptomatic adjuvant GM-CSF S or minimally U symptomatic R ProstVac-VF + V metastatic TRICOM + Standard of Care I CRPC adjuvant placebo V A (Planned No cross-over L N = 1200) Vector placebo + adjuvant placebo  Primary endpoint: OSClinicalTrials.gov. NCT01322490.
    39. 39. Conclusions Sipuleucel-T: a current treatment option – Asymptomatic or minimally symptomatic patients ProstVac-VF: entering phase III prechemotherapy Challenges – Sipuleucel-T: timing with regard to abiraterone – Integration of immunotherapy with chemotherapy and multiple other agents – An embarrassment of riches?
    40. 40. Hormone Refractory Prostate Cancer Multiple treatment options – Stop oral anti-androgens – Switch to another anti-androgen – Steroids – Ketoconazole – Megestrol acetate – Chemotherapy – ?immunotherapy – ?Target therapy
    41. 41. OS Benefit in Recent CRPC TrialsTrial/Agent Approved Disease State Comparator HR P ValueIMPACT[1] Chemo-naive Placebo 0.775 .032(Sipuleucel-T CRPCvaccine)TAX327[2] Chemo-naive Mitoxantrone 0.76 .009(Docetaxel) CRPC PrednisoneTROPIC[3] Post- Mitoxantrone 0.70 < .0001(Cabazitaxel) docetaxel Prednisone CRPCCOU-AA-301[4] Post- Placebo 0.646 < .0001(Abiraterone acetate) docetaxel Prednisone CRPC1. Kantoff PW, et al. N Engl J Med. 2010;363:411-422.2. Tannock IF, et al. N Engl J Med. 2004;351:1502-1512.3. de Bono JS, et al. Lancet. 2010;376:1147-1154.4. de Bono J, et al. N Engl J Med. 2011;364:1995-2005.
    42. 42.  Thanks for the attention
    43. 43. Case Study: Part 2 Same patient – non-mCRPC Enrolls in phase II study or oral TAK-700 (orteronel) Has a PSA response lasting 6 months Then PSA begins to rise: 4.6 → 7.5 → 11.2 ng/mL Testosterone: 2 ng/dL CT scan repeated: Remains normal Bone scan: New lesions left 5th rib and L1 vertebral body He remains asymptomatic – no bone pain – ECOG 0
    44. 44. Case Study: Part 2Discussion Question How would you manage this patient now?
    45. 45. Case Study: Part 3 Same patient – asymptomatic mCRPC Patient receives 3 infusions of sipuleucel-T PSA rises after 3 months, and again after 6 months CT scan: Para aortic lymphadenopathy (up to 3.8 cm) Bone scan: 2 rib, 2 vertebral, and 1 pelvic bone lesion Patient reports new rib and back pain (intensity 3/10) ECOG PS 0
    46. 46. Case Study: Part 3Discussion Question How would you manage this patient now?
    47. 47. Case Study: Part 4 Same patient – symptomatic mCRPC He receives docetaxel q3wks and denosumab q4wks Obtains PSA response and objective radiologic response After 8 cycles, stops docetaxel due to grade 3 neuropathy 4 months later, he has further PSA progression CT: New liver lesions (up to 4 cm) and lung lesions (8 mm) Bone lesions: Stable Has persistent grade 2 peripheral neuropathy ECOG PS 1
    48. 48. Case Study: Part 4Discussion Question How would you manage this patient now?
    49. 49. Case Study: Part 1  57-yr-old man – T3a PCa, Gleason 4+4 = 8, PSA = 8.2 ng/mL  Undergoes radical prostatectomy  Develops PSA recurrence with PSADT = 6 months  Started on leuprolide + bicalutamide, and responds for 18 months  Then develops rising PSA, despite bicalutamide withdrawal  PSAs: 4.2 → 5.6 → 7.2 ng/mL  Testosterone: 28 ng/dL  Bone scan and CT scan: Negative for metastatic disease•PSADT = prostate-specific antigen doubling time; CT = computed tomography.•NCCN, 2011.
    50. 50. Case Study: Part 1  57-yr-old man – T3a PCa, Gleason 4+4 = 8, PSA = 8.2 ng/mL  Undergoes radical prostatectomy  Develops PSA recurrence with PSADT = 6 months  Started on leuprolide + bicalutamide, and responds for 18 months  Then develops rising PSA, despite bicalutamide withdrawal  PSAs: 4.2 → 5.6 → 7.2 ng/mL  Testosterone: 28 ng/dL  Bone scan and CT scan: Negative for metastatic disease•PSADT = prostate-specific antigen doubling time; CT = computed tomography.•NCCN, 2011.

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