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Ca prostate presentation parth

  1. 1. Treatment of metastatic ca. Prostate & CRPC Dr. Parth Patel Surgical oncology resident, BMCHRC, Jaipur
  2. 2. • The core principle of treatment of advanced prostate cancer – to deplete androgens or inhibit signaling through the androgen receptor (AR). – Huggins and Hodges- close relationship of androgens with prostate tumor growth. showed that surgical removal of the testes or the administration of exogenous estrogen could induce • tumor regressions, • reduce the level of acid phosphatase • palliate symptoms of the disease.
  3. 3. • The palliative role of surgical adrenalectomy - 1945, later replaced by the first-generation enzymatic inhibitors of adrenal steroid biosynthesis (aminoglutethimide and ketoconazole). • LHRH agonists - 1980s • Nonsteroidal antiandrogens were introduced in the 1980s. • All these agents lower androgen levels, with the exception of the nonsteroidal antiandrogens that block the binding of androgens to the AR.
  4. 4. • Initial responses to castration therapy are quite favourable, with a significant clinical regression and rapid biochemical responses, as assessed by decline in S.PSA in 80–90% of patients with metastatic disease. • Despite a good initial response, remissions last on average 2-3 years, with eventual progression occurring despite castration.
  5. 5. • In these cases prostate cancer will progress to a castration- insensitive phase of disease (Castration-Resistant Prostate Cancer—CRPC) which carries a worse prognosis and translates into a survival time of 16–18 months in average from the beginning of progression. • Systemic therapies have also been an option in the management to these patients. However, chemotherapy is not well tolerated by all CRPC patients, who were often elderly men with limited bone marrow reserve and concurrent medical conditions
  6. 6. • a biologic agent (Sipuleucel-T), • a cytotoxic (Cabazitaxel), • a bone-seeking alpha-emitting radionuclide (Radium-223), • CYP17 inhibitor Abiraterone acetate that inhibits androgen biosynthesis in combination with prednisone and • a next generation antiandrogen, Enzalutamide, which is mechanistically unique from the first-generation compounds. • Denosumab, a monoclonal antibody that binds the cytokine RANKL (receptor activator of nuclear factor-κB ligand)
  7. 7. • Current methods of castration (or ADT) – LHRH agonists – LHRH antagonists – Orchiectomy –  Nonsteroidal antiandrogens
  8. 8. LHRH AGONISTS • LHRH agonists produce an initial rise in LH that increases testosterone levels, followed 1 to 2 weeks later by downregulation of LH receptors that results in a medical castration. • The initial rise in testosterone can flare the disease, precipitating or exacerbating symptoms such as pain, obstructive uropathies, and spinal cord compromise. • compared with oral estrogens, – Reduction in edema, thrombosis and thromboembolism, myocardial infarction, and stroke. • Leuprolide, goserelin, triptorelin, historelin- available in daily or monthly injection dosages or 3,4 ,6 or 12 monthly depot prepes.
  9. 9. LHRH ANTAGONISTS • castrate levels of testosterone in 48 hours without the initial rise making • At present, Degarelix, available as monthly subcutaneous injections, is the only LHRH antagonist that is approved in the United States. • DISADVANTAGE: – Higher rate of injection site reactions
  10. 10. ANTIANDROGENS • block the binding of testosterone to the AR. – the steroidal type I agents such as cyproterone acetate have progestational properties that suppress LH levels and lower serum testosterone; these are not widely used. – The non steroidal type II agents bind to the AR and act as competitive antagonists for ligands that might otherwise bind and activate the ligand- dependent transcriptional activity of the receptor
  11. 11. • Flutamide: shorter t1/2- used along with LHRH agonists to prevent initial flare. • Bicalutamide(50mg/day) and Nilutamide- T1/2 in weeks, so effective in once daily doses. • Do not reduce the LHRH secretions- testosterone levels continue to rise. • Not approved as monotherapy by US FDA.
  12. 12. Toxicity of ADT • “androgen deprivation syndrome” • hot flashes, • a decrease in libido, • erectile dysfunction, • impotence, • fatigue, anemia, • weight gain and alterations in fat metabolism, • loss of muscle mass and weakness, • bone loss, • a decrease in mental acuity, mood swings, personality changes, memory loss, depression, and insomnia
  13. 13. Toxicity of anti androgens • Elevations in hepatic enzymes, stomach upset and diarrhea, and pulmonary complications such as fibrosis; these toxicities are a rare class effect of the first-generation antiandrogens, which occur most frequently with nilutamide. • Gynecomastia and/or breast tenderness may also develop, which, if severe, might require a reduction mammoplasty.
  14. 14. CASTRATION RESISTANT CA. PROSTATE • Definition – disease progression despite androgen deplation therapy and may present as either a continues rise in S.PSA , progression of pre existing disease, and/or appearance of new mets. • The development of hormone resistance is virtually a universal issue that affects all patients treated with ADT. • Criterias : – Testosterone levels < 50 ng/ml – Biochem progression – Progressive metastasis – Progression despite cessation of ADT
  15. 15. Castrate Resistant Prostate Cancer • In the past, we used terms like – Hormone Refractory – Androgen Independent – Androgen Resistant • Now … Castrate Resistant Prostate Cancer (CRPCa) – Why?
  16. 16. • Even though patients have castrate levels of serum testosterone (50ng/mL), AR signalling is still happening – By our current methods of “castration”, they are resistant but these tumors are still responding to AR signalling.
  17. 17. Mechanism of development of CRPC Resistance mechanisms can be divided into 6 groups: (i) Increased Expression of Enzymes Involved in Steroid genesis. - - in CRPC patients, even castrate serum levels of androgen are still sufficient for AR activation and able to maintain cancer cells survival. - the intra tumoral levels of testosterone in CRPC patients are equal of those found in non castrate patients. The source of these androgens is thought to be derived from the synthesis of androgens directly in prostate cancer cells due to an up regulation of the enzymes.
  18. 18. (ii) Increased Expression of AR. - The activated AR pathways has been postulated as a result of genetic phenomena that promotes increased sensitivity of AR. (iii) AR Gene Mutations and Altered Ligand Specificity. - While the androgens are the main factors of tumor growth and AR signaling, the presence of AR mutations leads to its activation by nonandrogenic steroid molecules and antiandrogens.
  19. 19. (iv) Downstream Signaling Receptor for Androgens. - One of the most important mechanisms. (v) Bypass Pathways. - The induction of bypass pathways independent of AR, is an important mechanism of castration resistance, that can overcame apoptosis induced by androgen- deprivation therapy.
  20. 20. (vi) Stem Cells. - Prostatic cancer stem cells are rare and undifferentiated cells that do not express AR on their surface, being independent of androgens to survive. - These cells can be responsible for maintaining tumor growth and development, because they are able to survive under androgen- deprivation therapy.
  21. 21. Clinical considerations • A complete disease evaluation is required to estimate the outcome and to make therapeutic decisions. • Critical baseline components – Extent of disease – Mode and site of progression (rising PSA level alone, new bone metastasis, visceral and nodal metastasis) – Presence or absence of symptoms – Response and compliance to prior endocrine treatment.
  22. 22. Disease Progression
  23. 23. Metastatic Castration-Resistant Disease
  24. 24. Clinical considerations • Routine evaluation of serum testosterone levels may provide important information for the choice of treatment. • To suspect treatment noncompliance or if the choice of prior treatment involved regimens known not to result in a sustained suppression of serum testosterone to castrate levels (e.g., monotherapy with nonsteroidal antiandrogens, low- dose estrogens, or 5α-reductase inhibitors).
  25. 25. • The current treatment options for patients with CRPC can be divided in different groups such as A) Discontinuation of antiandrogens B) Secondary hormonal therapies, C) Bone-Targeted Therapy: Bisphosphonates and Denosumab D) Chemotherapy agents, E) Vaccine-based immune therapy, F) Radiotherapy and G) Novel targets.
  26. 26. • 1st step ,A)Discontinuation of antiandrogens (both steroidal and non steroidal) can result in short term clinical responses expressed by decreases in PSA levels, symptomatic benefits, and, less frequently, objective improvements in soft tissue and bone metastasis in a small proportion of patients. • serial monitoring of PSA levels for a period of 4 to 8 weeks before embarking on the next therapeutic maneuver. • 30% of the patients have a drop in PSA after discontinuing antiandrogens.
  27. 27. • 2nd step : B) second-line hormonal manipulation or cytotoxic chemotherapy • Agents that have been reported to produce some benefit in this setting include, – Corticosteroids- oral glucocorticoids at lower doses (10 mg/day) can result in temporary PSA responses for 25% of the patients, presumably due to adrenal androgen suppression – Diethylstilbestrol- Diethylstilboestrol (DES), a synthetic estrogen, as well as the other estrogens, suppresses the HPA and it reduces ≥50% the total PSA in 26% to 66% of patients with CRPC. However, the thromboembolic toxicity limited is use – Ketoconazole– in CRPC patients after antiandrogen withdrawal because it inhibits cytochrome P-450 enzyme-mediated steroidogenesis in testes and adrenal glands and when given at high- dose (1200 mg/day). it resulted in ≥50% PSA reduction in 27% to 63%. – Aminoglutethimide – Abiraterone acetate – MDV3100 (Enzalutamide)
  28. 28. • Abiraterone acetate – - a prodrug of abiraterone, is potent and highly selective inhibitor of androgen biosynthesis that blocks cytochrome P450 c17 (CYP 17), a critical enzyme in testosterone synthesis, thereby blocking androgen synthesis by the adrenal glands and testes and within prostate tumor.
  29. 29. Abiraterone Phase III Trials: COU-AA-301 and COU-AA-302 301 eligibility criteria: • Progressive mCRPC pts who failed a docetaxel regimen ± another chemotherapy 302 eligibility criteria: • Progressive chemo-naïve mCRPC, asymptomatic or mildly symptomatic Abiraterone 1000mg qd+ prednisone bidR A N D O M I Z E (N=1195) 2:1 Placebo qd+ prednisone bid Co-primary endpoints: OS + rPFS by central review 1. de Bono et al. N Engl J Med. 2011;364:1995-2005. 2. Ryan CJ, et al. N Engl J Med. 2013;368:138-48. 1:1 (N=1088) Primary endpoint: OS Median OS Adverse Events Abiraterone Placebo Abiraterone COU-AA-3011 14.8 mo 10.9 mo Fluid retention and edema, hypokalemia, cardiac disorders(P < 0.0001) COU-AA-3022 Not reached 27.2 mo Mineralocorticoid-related + abnormalities on liver- function testing(P = 0.01)
  30. 30. • second-generation antiandrogens • One such drug is MDV3100 (Enzalutamide), a potent oral nonsteroidal AR antagonist. • Importantly, MDV3100 remains a potent antagonist of the AR in the castration-resistant state, even in the setting of overexpressed or constitutively activated AR. • No partial agonistic action .
  31. 31. Enzalutamide Phase III AFFIRM Trial • Median OS: 18.4 mo enzalutamide, 13.6 mo placebo (P < 0.0001) • Adverse events: Enzalutamide group reported 45% of patients with any ≥ grade 3 adverse event vs 53% with placebo Eligibility criteria: • CRPC pts who progressed during or after treatment with a docetaxel-based regimen Enzalutamide 160 mg qdR A N D O M I Z E (N=1199) 2:1 Placebo qd Primary endpoint: OS Scher HI et al. N Engl J Med. 2012;367:1187-97. mOS=median overall survival.
  32. 32. • Hormonal > cytotoxic chemotherapy for those patients with relatively limited metastatic disease who remain asymptomatic at the time of disease progression (eg. Rising serum PSA value without other clinical manifestations).
  33. 33. C) Bone-Targeted Therapy: Bisphosphonates and Denosumab.
  34. 34. • Reduce bone resorption by inhibiting osteoclastic activity and proliferation. • Zoledronate is a potent intravenous bisphosphonate first approved for the treatment of hypercalcemia and decreased bone mineral density in postmenopausal women. • In patients with progressive castration-refractory disease and bone metastases zoledronate was shown to reduce the incidence of skeletal-related events (eg. Pain, fractures) • Standard dose: 4 mg iv 3-4 wks apart
  35. 35. • Side effects: fatigue, myalgias, fever, anemia, and mild elevation of the serum creatinine concentration. • Hypocalcemia has been described, and concomitant use of oral calcium supplements (1500 mg/day) and vitamin D (400 units/ day) is often recommended. • An unusual complication of zoledronate is the development of severe jaw pain associated with osteonecrosis of the mandibular bone • OTHER: Alendronate, Etidronate, Ibandronate and Clodronate
  36. 36. RANKL Inhibitors • Monoclonal antibodies to RANKL significantly inhibit osteoclastic function in vitro and in vivo. • Denosumab, a fully human monoclonal antibody against RANKL • Common toxicities of denosumab include fatigue, nausea, hypophosphatemia, hypocalcemia and osteonecrosis of the jaw (2%) • Prophylactic calcium and vitamin D supplementation is strongly encouraged.
  37. 37. -In a phase III study denosumab, a human monoclonal antibody against RANKL, was compared with zoledronic acid for prevention of skeletal-related events. The results showed advantage to denosumab, representing another treatment opportunity for CRPC patients.
  38. 38. • advantage that it does not require dose adjustment or monitoring for renal impairment. • The recommended dose of Denosumab is 120 mg given by subcutaneous injection every 4 weeks.
  39. 39. D) Chemotherapy. • A first step forward in the chemotherapeutic management of CRPC came with mitoxantrone, previously shown modest symptomatic benefits but with minimal evidence of objective antitumor activity • In addition, mitoxantrone appeared to have its maximal palliative effect in combination with low-dose corticosteroids. • The combination resulted in significant improvements of various quality of life parameters, including pain, but survival was not significantly improved in either trial. - Docetaxel is the only approved chemotherapy that has been shown to prolong survival among men with metastatic CRPC.
  40. 40. TAX-327 TRIAL • Compared – docetaxel 75 mg/m2 every 3 weeksfor up to 10 cycles (group 1), – docetaxel 30 mg/m2 weekly for 5 cycles (group 2), – mitoxantrone 12 mg/m2 every 3 weeks for 10cycles (group 3). – Prednisone (10 mg daily) was added to all regimens. • The primary end point was overall survival; • secondary end points included changes in pain, PSA, tumor response rate and overall QOL.
  41. 41. • Median survival for the respective arms was 18.9 months, 17.4 months, and 16.5 months, respectively, which led to the approval of docetaxel plus prednisone for “androgen- independent (hormone-refractory)”disease. • The 2.4-month difference in median survival (18.9 months versus 16.5 months) for the every- three-week docetaxel versus the mitoxantrone schedule established the every-three-week regimen as the standard.
  42. 42. • Toxicity in the 3-weekly versus weekly docetaxel groups was notable for more hematologic toxicity in the every-3-week group but slightly lower rates of nausea and vomiting, fatigue, nail changes, hyperlacrimation, and diarrhea. • Neuropathy was slightly more common in the every-3-week group
  43. 43. SWOG 9916 STUDY • 770 patients to – Estramustine (280 mg orally three times daily on days 1 to 5), docetaxel (60 mg/m2every 3 weeks), and dexamethasone (60 mg every 3 weeks) versus – Mitoxantrone and prednisone (5 mg twice a day) to a maximum of 12 cycles with no crossover at progression. • The primary end point was overall survival. • PSA declines, soft tissue response, and PFS were secondary end points.
  44. 44. • 2-month difference in median survival was observed for docetaxel/estramustine (17.5 months versus 15.6 months), representing a 20% reduction in mortality. • A higher incidence of neutropenia and fever, nausea, vomiting, and vascular events with docetaxel/estramustine was noted despite the lower dose of docetaxel. • The results further supported docetaxel 70 mg/m2 every 3 weeks as the standard regimen.
  45. 45. • Till 2010 the treatment for docetaxel resistant CRPC was lacking until FDA approved 2nd drug, CABAZITAXEL • Cabazitaxel, a novel tubulin-binding taxane, is the first chemotherapy shown to improve survival in patients with docetaxel-refractory metastatic castration resistant prostatic cancer. • Cabazitaxel was shown to be active in both docetaxel- sensitive tumors as well as those with primary or acquired docetaxel resistance.
  46. 46. The TROPIC trial • a randomized phase III study compared cabazitaxel plus prednisone versus mitoxantrone plus prednisolone, in patients with docetaxel-refractory prostate cancer. • The cabazitaxel arm showed an improvement in median PFS (2.8 months versus 1.4 months) (P < 0.0001), median OS (15.1 months versus 12.7 months), and lower risk of death (hazard ratio 0.70) (P < 0.0001)
  47. 47. • Administered by intravenous infusion every 3 weeks at escalating doses of 10 to 25 mg/m2 • The principal dose-limiting toxicity was neutropenia.
  48. 48. E) External Beam Radiotherapy, Hemibody RT, and Radioisotope Pharmaceuticals. - Radioisotope pharmaceuticals which may be associated with less toxicity and are more appropriated for patients with multiple painful lesions. - These radioisotopes are used in men with advanced prostate cancer with osteoblastic bone metastasis. - These patients are often characterized by a high ratio of bone to soft tissue metastases. - In order for these patients to be treated with radioisotopes the presence of uptake on bone scan due to metastatic disease at sites that correlate with pain is necessary.
  49. 49. • MC : strontium-89 (89Sr) and samarium-153 (153Sm). • Radium-223 is an alpha-emitting pharmaceutical agent that showed to improve survival in a phase III study [56]. Compared with placebo, Radium-223 was associated with improved overall survival
  50. 50. F)Vaccines-Based Immunotherapy. -Sipuleucel-T (Provenge, APC8015) is an autologous dendritic cell vaccine, consisting of autologous peripheral blood mononuclear cells (PBMCs). -In the first two randomized trials, sipuleucelT, the primary endpoint was not accomplished since these studies did not show a significant effect on the time to disease progression comparing with placebo. Despite this, the hazard ratios were in favour of sipuleucel-T.
  51. 51. - IMPACT trial - a phase III, randomized trial, - asymptomatic or minimally symptomatic metastatic CRPC. - Result: 4.1-month improvement in median overall survival and an improvement in the rate of 3-year survival (31% versus 23%) in sipuleucel-T arm, with limited toxicity. - No effect on time to progression which was the primary endpoint.
  52. 52. MONITOR THE RESPONSE • PSA doubling time (PSADT) predicts for the rapidity of bone scan progression and survival • Patients with PSADTs shorter than 3 months have a particularly rapid clinical course and should be considered for more aggressive management approaches.
  53. 53. Palliative Management • Pain control: – EBRT – IV corticosteroids – Biphosphonates – Calcitonin – TCA – Chemotherapy – Surgical intervention
  54. 54. NEWER AGENTS • PROSTVAC- is a cancer vaccine consisting of a recombinant vaccinia vector as a priming immunization with subsequent multiple booster vaccinations, using a recombinant fowlpox vector. • Ipilimumab • Cabozatinib • Dasatinib • Bevasizumab • Sunitinib
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