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  • TROPIC slide deck. Slide5

I. Tannock - New developments in the systemic treatment of advanced prostate cancer I. Tannock - New developments in the systemic treatment of advanced prostate cancer Presentation Transcript

  • ECLU May 2011
  • ECLU May 2011
  • New developments in the systemic treatment of advanced prostate cancer Ian F Tannock MD, PhD, DSc Princess Margaret Hospital and University of Toronto 3
  • Potential conflicts of interest
    • I have advised multiple companies about design of trials for prostate cancer for which I have received contributions to my research fund.
    • I have chaired international company-sponsored trials for hormone-refractory prostate cancer (TAX-327, VENICE)
    • I do not accept personal remuneration from companies
    4
  • Outline of Presentation
    • Advances in hormonal (androgen-deprivation) therapy (ADT)
      • Intermittent therapy
      • Toxicity of ADT
      • New hormonal agents
    • Advances in chemotherapy
      • Trials of docetaxel + other agents
      • Post-docetaxel
    • Prevention of skeletal events
    • Immunotherapy
    5
  • A hypothetical patient- Mr Eriksson
    • A 68 year old man post radical prostatectomy 3 years ago for a Gleason 7 prostatic cancer.
    • Now has a 3-month history of pain in several bones with a positive bone scan and PSA=245ng/ml
    • Which treatment should he receive?
    • LHRH agonist (e.g. goserelin; leuprolide) with short course of andiandrogen to prevent flare
    • Antiandrogen alone (e.g. bicalutamide)
    • Combined androgen blockade (LHRH agonist + antiandrogen)
    • Intermittent hormonal therapy
    6
  • The patient-based meta-analysis showed no significant benefit of MAB after 8000+ pts and 27 trials MAB is expensive, has increased toxicity and should not be used 7
  • Studies in animals show that intermittent ADT delays time to castrate-resistance Sato et al: J Steroid Biochem Molec Biol 1996;58:139-46 Several clinical trials now support the use of intermittent therapy for men with prostate cancer who have an excellent response to initial therapy 8
  • Randomized trials of intermittent vs continuous hormonal therapy 9 Trial N Setting Treatment Result De Leval: Clin Prost Cancer 2002 68 T3-4, N+, M+ goserelin+ flutamide  Time to CRPC Miller ASCO 2007 335 N+, M+ goserelin + bicalutamide Similar time to CRPC better QoL Thun AUA 2007 167  PSA after RP leuprolide Similar time to CRPC better QoL Calais da Silva Europ Urol 2009 626 T3-4, N+, M+ triptorelin + cyproterone Similar time to CRPC & survival, better QoL Klotz (NCIC PR7) ASCO GU 2011 1386  PSA after RP/RT LHRH agonist Similar time to CRPC & survival, better QoL
  • Time to Progression (Miller et al, 2007) Intermittent: median 16.6 months P = 0.17 Continous: median 11.5 months 10
  • Summary-1 Selection of primary ADT for men with advanced prostate cancer
    • Orchiectomy or continuous LHRH agonist has been standard. (Short course of a peripheral anti-androgen should be used to prevent flare with LHR agonist)
    • Combined androgen blockade should not be used
    • Strong evidence to support intermittent hormonal therapy in men with good initial PSA response
    • At progression about 30% of men will have a brief response on adding an anti-androgen (e.g. bicalutamide)
    • About 20% of those who respond may respond to antiandrogen withdrawal
    11
  • Your views are important
    • Remember that you can ask questions and send comments at any time
    Click here to e-mail a question
  • Mr Eriksson’s Treatment
    • He receives an LHRH agonist with short term bicalutamide to prevent flare
    • He is pain free within 2 weeks, and his PSA declines
    • But he does have some side effects.....
    ECLU May 2011
    • Impotence
    • Gynecomastia
    • Hot flashes
    • Loss of muscle and bone
    • Anemia
    • Thrombocytopenia
    • Increased risk of cardiovascular events
    Which of these -> is NOT a known side effect of hormonal therapy? 13
  • Prevention of Bone Loss for men on hormonal therapy
    • Exercise is probably the best protection against loss of bone and muscle
    • All men receiving ADT should be taking calcium and vitamin D
    • Several randomised trials have shown that bisphosphonates can prevent bone loss
    Placebo 40 men starting ADT Zoledronate 4mg every 12 mos e.g. Michaelson et al: JCO 2007;25:1038-42 3.1% decrease in bone density 4.0% increase 14
  • There is increasing evidence that ADT raises insulin levels and may increase diabetes and cardiovascular disease >73,000 men age>65 treated for localized Ca prostate 1992-1999, observed through 2001 >1 in 3 received ADT (Keating et al, J Clin Oncol 2006;24:4448-56) Other recent series have confirmed these effects 15 Events per 1000 person-years Diabetes CHF MI Sudden death No treatment 20.9 61.3 10.9 9.0 LHRH agonist 29.0 72.3 13.6 12.9 Orchiectomy 24.5 63.3 13.2 12.5
  • Summary-2 Androgen-deprivation therapy (ADT) can cause:
    • Impotence, gynecomastia and hot flashes: Low-dose medroxy-progesterone acetate can relieve hot flashes
    • Anemia (usually low grade) & loss of muscle mass, leading to fatigue and  QoL: Encourage exercise
    • Bone loss, with  risk of fracture. Men on ADT should have baseline bone density & take Ca ++ and vit D: Bisphosphonates should be used for those with bone loss
    • Metabolic syndrome and  cardiac events. Use cautiously in men with pre-existing diabetes or cardiac history
    ECLU May 2011 Less is better! No role for ADT in asymptomatic men with slowly rising PSA before or after local treatment. Use intermittent therapy where feasible 16
  • Castration-resistance
    • Mr Eriksson has  pain and  PSA after 1  & 2  ADT (LHRH agonist followed by addition and withdrawal of bicalutamide). He might still respond to:
    • Other anti-androgens (e.g. nilutamide, flutamide)
      • Inhibitors of steroid synthesis (e.g. ketoconazole)
      • Estrogens such as DES
      • Glucocorticoids such as dexamethasone
      • Thus “Castration-resistance” is more appropriate than “Hormone-refractory”
    Studies have shown  androgen levels within prostatic tissue (including cancer) which can stimulate androgen pathways in the face of low circulating androgens 17
    • Increased emphasis on “time to event” endpoints as compared to “response” endpoints
    • Early changes in PSA or pain to be ignored (unless overwhelming evidence of clinical progression) and treatment to be continued for at least 12 weeks
    • No need to wait for anti-androgen withdrawal if there was no response to adding the anti-androgen
    • Decreased emphasis on bone scans and rigorous requirements for defining progression by bone scan
    18
  • Two promising new agents for hormonal treatment of CRPC
    • Abiraterone acetate, an inhibitor of androgen synthesis
    • MDV-3100, an irreversible inhibitor of the androgen receptor
    • Both drugs have shown high rates of PSA response and delay to progression in phase II trials for men with CRPC, both pre- and post-chemotherapy
    • Large RCTs have evaluated, or are in progress:
    • Abiraterone + prednisone vs prednisone
    • MDV-3100 vs placebo
    • in both pre and post-chemotherapy settings
    19
  • Abiraterone acetate: Attard et al, JCO 2008 ;26: 4563; de Bono et al, ESMO 2010 ECLU May 2011 20
  • 21
  • MDV3100 (Tran et al: Science 2010;324:787-90)
    • Derived from screen of anti-androgens that retain activity with  expression of the AR
    •  binding affinity to AR
    •  nuclear translocation of AR
    •  binding of DNA to androgen response elements
    •  recruitment of co-activators
    22
  • Summary-3: New hormonal agents are active in many men with CRPC
    • Androgen-dependent pathways remain active in many men with CRPC (resistant to 1  and 2  lines of ADT)
    • Testosterone present in prostate tumours despite castrate levels in the circulation
    • New agents are active in men with CRPC either before or after chemotherapy
    • Abiraterone inhibits androgen synthesis and prolongs median survival by 4 months in men who received prior chemotherapy: recently approved by FDA
    • MDV-3100 is an irreversible anti-androgen with similar levels of activity in phase II trials
    • Other drugs are in the pipeline (e.g. TAK-700)
    23
  • How should Mr Eriksson be managed for castration-resistant prostate cancer (CRPC)
    • Recognise that he has incurable cancer and Quality of life is important
    • Optimise Mr Eriksson’s pain control with regular dosing of narcotic medication, such as morphine
    • Give regular laxatives to control the constipation that will be caused by morphine
    • Give local radiotherapy to the right hip, his dominant site of pain
    • Consider chemotherapy for men with diffuse symptoms or rapid PSA progression
    24
  • Chemotherapy for castration-resistant prostate cancer
    • Early trials showed that mitoxantrone + prednisone gave better pain control and QoL compared to prednisone alone (Tannock et al, JCO 1996:14;1756-64)
    More recent trials found  PSA and  pain, and  survival with docetaxel and prednisone (Tannock et al, NEJM 2004;351:1502-12 Petrylak et al, NEJM 2004;351:1513-20 Berthold et al, JCO 2008;26:242-5) N=1006 25
    • He has relief of pain and by the 3 rd course of treatment he is able to stop taking morphine
    • His PSA declines steadily after an initial increase but begins to rise again after 8 courses
    • He has minimal acute toxicity but is tired and develops numbness in his hands and feet
    Mr Eriksson is treated with docetaxel and prednisone 26 TAX-327 2  endpoints Docetaxel q 3wk Docetaxel wkly Mitox q 3wk Pain Response Rate 34.6% p=0.01 31.2% p=0.08 21.7% PSA Response Rate 45.4% p=0.0005 47.9% p<0.0001 31.7% QOL Response rate 21.9% p=0.009 22.6% p=0.005 13.1%
  • Might Mr Eriksson have greater benefit if treated with a molecular targeted agent in combination with docetaxel?
    • Completed RCTs evaluating docetaxel plus:
      • High-dose calcitriol (DN-101)
      • Bevacizumab
      • GVAX (vaccine against common prostate cancer antigens)
      • Atrasentan or Zibentan (Endothelin A antagonists)
      • Dasatanib (src/SFK inhibitor)
      • … . have all been negative
    • Other RCTs are evaluating docetaxel plus:
      • Aflibercept (VEGF-Trap)
      • Lenolidamide (Thalidomide analogue)
      • Custirsen (OGX-011, anti-clusterin, pro-apoptotic)
    27
  • The ASCENT2 study: Docetaxel plus high-dose calcitriol (DN-101) versus docetaxel (plus prednisone) for progressive CRPC (Scher et al, ASCO 2010) Study recruited 953 men. A placebo-controlled phase II study had suggested that DN-101 increases survival Trial was stopped early after an interim analysis showed more deaths in the DN-101 arm 28 DN-101 Control P-value Median survival (months) 16.8 19.9 0.019 (0.002 by logrank) Deaths due to prostate cancer 142 108 Deaths due to other cause 32 30 Dose modifications for docetaxel 229 160
  • Docetaxel + prednisone +/- bevacizumab for CRPC (Kelly et al, ASCO, 2010) Increase in OS and PFS are virtually identical to overview of 3 breast cancer trials – considered positive because primary endpoint was PFS 29 Endpoint DP + B (N=524) DP (N=526) HR P-value OS (mos) 22.6 21.5 0.91 0.18 PFS (mos) 9.9 7.5 0.77 <0.0001 PSA-RR 69.5% 57.9% 0.0002 Toxicity 
  • Summary-4: First-line chemotherapy for men with CRPC
    • Before considering chemotherapy, optimise the patient’s pain control, and consider local radiotherapy for local pain
    • Mitoxantrone and prednisone improve pain in a subset of men with CRPC. The drug is well tolerated
    • Docetaxel (q 3 weeks) given with prednisone improves median survival by ~3months (compared to mitoxantrone), and can improve pain and QoL in symptomatic patients
    • Several molecular targeted agents have been evaluated with docetaxel, but have not improved survival. Trials with other agents are in progress
    • Substantial randomised phase II studies can give misleading results
    30
  • Your views are important
    • Remember that you can ask questions and send comments at any time
    31 Your views are important Remember that you can ask questions and send comments at any time Click here to e-mail a question
  • The TROPIC study: cabazitaxel or mitoxantrone with prednisone for metastatic CRPC previously treated with docetaxel (De Bono et al, ASCO 2010) Time (months) Proportion of OS (%) The study met its primary objective (  survival) N=755 Should Mr Eriksson receive 2 nd -line chemotherapy? 32 0 6 12 18 24 30 MP CBZP Median OS (months) 12.7 15.1 Hazard ratio 0.72 95% CI 0.61–0.84 P -value <.0001 Censored MP CBZP Combined median follow-up: 13.7 months 100 80 60 40 20 0
  • Important secondary results of the cabazitaxel trial Concerning! Major impairment to quality of life 33 Efficacy MP CBZP p-value Comment Tumor response (%) 4.4 14.4 0.0005 PSA response (%) 17.8 39.2 0.0002 MP consistent with other studies Pain response (%) 7.8 9.2 0.63 Disappointing ! Toxicity MP CBZP Comment Toxic death 7 (1.9%) 18 (4.9%) Neutropenic sepsis 1.3% 7.5% Diarrhea (≥ grade III) 0.3% 6.2% Neuropathy (%) ?????
  • Summary-5: Second-line chemotherapy for men with CRPC
    • Mitoxantrone has often been used second line, and is associated with ~15% PSA RR after docetaxel
    • Some patients may respond to retreatment with docetaxel after an interval off-treatment
    • Satraplatin was shown in a RCT to increase time to progression (but not survival) compared with prednisone alone – it was not approved by the FDA
    • Cabazitaxel was shown to improve survival in an RCT compared to mitoxantrone, but led to high toxicity
    • Of newly approved systemic agents abiraterone would be first choice after docetaxel
    34
  • Zoledronate Study (Saad et al, JNCI 2002;94:1458-68 & 2004;96:879-82)
    • 8mg dose caused renal insufficiency and dropped to 4mg – but no sig difference to placebo for this arm
    •  bone events with 4mg dose (44%) compared to placebo (33%, p=0.02) but no difference in QoL
    • More low-grade toxicity with zoledronate
    Should Mr Eriksson have received an agent to reduce fractures and other bone events 35
  • Is the RANK-ligand inhibitor Denosumab superior to Zoledronate?
    • Denosumab is a fully humanized monoclonal antibody against RANK-L given subcutaneously
    • Evaluated in a RCT of 1900 pts Fizazi et al, Lancet 2011;377:813-22
    • Longer time to skeletal-related events
    • Convenience of s.c. administration
    • Adverse events were similar in both arms.
    • Drug is more expensive than zoledronate
    36
  • Summary 6- Use of zoledronate or denosomab with chemotherapy
    • Useful drugs to decrease bone events in selected patients
    • Some cases of osteonecrosis of the jaw
    • Annual zoledronate is sufficient to prevent osteopenia in men on long-term ADT - no evidence to support use at 3-weekly intervals
    • We are conducting a trial to evaluate duration of suppression of bone turnover after zoledronate
    • Optimal interval for administration of denosomab is unknown
    • Doubtful that either drug is cost-effective
    37
  • On his next visit to clinic, Mr Eriksson is failing, but his wife brings a newspaper article about Sipuleucil-T a type of immunotherapy. “What does this treatment involve” she asks, “and could it be used to save my husband’s life?” Men with CRPC undergo leukophoresis Patient’s antigen-presenting cells (APC) cultured in presence of prostatic acid phosphatase (PAP) linked to G-CSF Ship to central facility Ship to patient’s treatment facility Infuse into patient Process is repeated 3 times at 2-week intervals 38
  • Sipuleucel-T Estimated cost = $93,000 39
  • Summary 7- Immunotherapy for prostate cancer
    • Sipuleucil-T represents first improvement of survival from use of immunotherapy
    • Consistent results across 3 randomised trials
    • Stimulation of immune response demonstrated in men receiving sipuleucil-T
    • Results are “strange” because of improved survival with no effect on tumour response or progression
    • Controls in the RCTs receive infusion of cells not exposed to PAP antigen - could this be harmful?
    • Procedure is logistically difficult and very expensive
    40
  • Thanks to our international fellows who stimulate my ideas (but are not responsible for them).....and have done much of the work Especially: Dominik Berthold Bostjan Seruga & Saroj Niraula 41
  • ECLU May 2011
  • ECLU May 2011
  • ECLU May 2011