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Genitourinary tumours: prostate and non prostate

Genitourinary tumours: prostate and non prostate. Patricia Walcott, BSc (Hons), MSc Medical Science Liaison Medical Ipsen Ltd. The following contains scientific information on unapproved indications.

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Genitourinary tumours: prostate and non prostate

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  1. Genitourinary tumours: prostate and non prostate Patricia Walcott, BSc (Hons), MSc Medical Science Liaison Medical Ipsen Ltd The following contains scientific information on unapproved indications. This is a summary of the selected genitourinary tumour data presented at ESOU and is not all encompassing April 2016

  2. A systematic review and meta-analysis of randomised trials of neoadjuvant hormone therapy for localised and locally advanced prostate carcinoma. Shelley MD and al., Cancer Treat, 2009; 35: 9 – 17 • Analysis of 10 randomised trial on NHT in locally advanced PCA • Significant improvement of: • positive surgical margins RR: 0,49 p<0.00001 • organ confinement RR: 1,63 p<0.001 • lymph node invasion RR: 0,49 p<0.02 • BUT: no benefit in overall or cancer specific survival ESOU 2016: Prostate Cancer Androgen Receptor Pathway Inhibitors in locally advanced PCA : Latest results D. Pfister, Cologne (DE) Rational of neoadjuvant therapy 2 challenges in treatment of high risk disease • Local control of the primary tumour • Systemic control of microscopic metastatic disease Primary goal of neoadjuvant therapy • Downstaging locally advanced PCa to facilitate resection • In-vivo observation of treatment response • Improvement of long-term survival Androgen Receptor Pathway Inhibitors in locally advanced PCA: Latest Results Presented D. Pfister, Cologne (DE) at ESOU16 15-17 Jan 2016

  3. Drawbacks of neoadjuvant ADT: biological response and resistance might be the reason for non-improvement of long-term outcome Androgen Receptor Pathway Inhibitors in locally advanced PCA: Latest Results Presented D. Pfister, Cologne (DE) at ESOU16 15-17 Jan 2016

  4. Neoadjuvant ADT for 0, <3, 3 to 6, 6 to 9 months prior to RP • Comparison of biopsy and radical prostatectomy specimens • Intraprostatic androgen levels and gene expression analysis of androgen related genes Results • Significant reduction of intraprostatic testosterone and DHT by 75% • Significant alteration of androgen dependent genes • Significant downregulation of several AR-responsive genes • No alterations in AR of PSA-genes • No significant reduction in AR and PSA expression Androgen Receptor Pathway Inhibitors in locally advanced PCA: Latest Results Presented D. Pfister, Cologne (DE) at ESOU16 15-17 Jan 2016

  5. Abiraterone: CYP17 Inhibition Adapted from Attard G et al. J Clin Oncol 2008 Androgen Receptor Pathway Inhibitors in locally advanced PCA: Latest Results Presented D. Pfister, Cologne (DE) at ESOU16 15-17 Jan 2016

  6. Enzalutamide: AR inhibition T-testosterone Inhibition of AR signalling at three levels: Blocks binding of testosterone to the AR Inhibits nuclear translocation of AR Inhibits binding of the AR to DNA Adapted from Tran C et al. Science 2009: Watson PA et al. Proct Natl Acad Sci USA 2010

  7. Leuprolide x 12 weeks Biopsy Newly Diagnosed Prostate Cancer cT3-4 or Gleason ≥7 (4+3) or PSA >10 ng/mL or PSA velocity >2 ng/mL/year Radical Prostatectomy Leuprolide + Abiraterone + Prednisone x 12 weeks Leuprolide + Abiraterone + Prednisone x 12 weeks Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase II neoadjuvant study. Taplin ME et al., J Clin Oncol 2014; 32: 3705 – 3715 N=58 patients with high risk PCA Androgen Receptor Pathway Inhibitors in locally advanced PCA: Latest Results Presented D. Pfister, Cologne (DE) at ESOU16 15-17 Jan 2016

  8. A B LHRHa + 12 w eeks AA LHRHa + 12 w eeks AA 1.0 100 p<001 LHRHa + 24 w eeks AA LHRHa + 24 w eeks AA p<001 0.8 p<001 75 p<001 Pregnenolone (pg/mg) 0.6 Progesterone (pg/mg) 44 533 50 38 313 35 315 0.335 0.335 0.305 0.4 25 0.2 0.072 5 632 0 0 LHRHa+AA LHRHa+AA LHRHa+AA LHRHa LHRHa LHRHa LHRHa+AA LHRHa+AA LHRHa+AA LHRHa+AA LHRHa+AA LHRHa+AA LHRHa+AA LHRHa LHRHa+AA LHRHa+AA 24weeks 24weeks 24weeks 12weeks 12weeks 12weeks 24weeks 12weeks C p=0.0215 LHRHa + 12 w eeks AA D LHRHa + 12 w eeks AA 40 0.15 p<001 p=0.0029 LHRHa + 24 w eeks AA LHRHa + 24 w eeks AA p<001 30 0.098 0.10 DHEA (pg/mg) 20 349 0.071 0.061 20 Testosterone (pg/mg) 0.058 0.05 10 0.455 0.649 0.576 0 0 LHRHa+AA LHRHa+AA LHRHa LHRHa LHRHa+AA LHRHa+AA LHRHa+AA LHRHa+AA 24weeks 24weeks 12weeks 12weeks E F LHRHa + 12 w eeks AA LHRHa + 12 w eeks AA 40 4 p<001 p<001 LHRHa + 24 w eeks AA LHRHa + 24 w eeks AA p<001 p<001 30 3 Dihydrotestosterone pg/mg) Δ4-androstene-3,17-dione (pg/mg) 20 2 1.307 0.261 10 1 0.060 0.058 0.194 0.180 0.190 0.0071 0 0 Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase II neoadjuvant study Taplin ME et al., J ClinOncol 2014; 32: 3705 – 3715 Significant reduction of median tissue androgen levels via CYP17 inhibition Androgen Receptor Pathway Inhibitors in locally advanced PCA: Latest Results Presented D. Pfister, Cologne (DE) at ESOU16 15-17 Jan 2016

  9. Additional results: • Still high percentage of pT3, pN1 and positive surgical margins • Still high percentage of residual tumour burden even after 24 weeks of neoadjuvanttreatment • No significant side effects of treatment • No negative impact on surgical morbidity

  10. ClinicalTrials.gov.identifier NCT01547299 Enzalutamide + Leuprolide + Dutasteride x6 months Newly Diagnosed Prostate Cancer Minimum of 3 cores Gleason ≥ 4+3+7 or PSA > 10ng/ml Radical Prostatectomy Leuprolide x6 months Androgen Receptor Pathway Inhibitors in locally advanced PCA: Latest Results Presented D. Pfister, Cologne (DE) at ESOU16 15-17 Jan 2016

  11. Summary • No general indication for neoadjuvant ADT in locally advanced PCA • Individual decision in large tumours to facilitate local treatment • No AR pathways inhibitors • Feasibility studies positive • No oncological outcome data • Still significant tumour burden after neoadjuvant therapy • Far away from clinical routine Androgen Receptor Pathway Inhibitors in locally advanced PCA: Latest Results Presented D. Pfister, Cologne (DE) at ESOU16 15-17 Jan 2016

  12. Intermittent hormone therapy: Not a standard for many urologists and oncologists. Why?F.Calais Da Silva, Lisbon (PT) • In Real Life patients do stop taking medication when: • Feel well • Secondary effects • Economics • But still low PSA and no clinical regression • The basic idea for intermittent hormonal therapy is the fact that long-term castration stimulates prostate cell apoptosis • After an average period of 24 months, the tumour relapses, characterised by a castrate-dependent state of growth • Experimantal data indicate that castrate dependent progression may begin early after castration, coinciding with the cessation of androgen-induced differentiation of stem cells

  13. It has been suggested that stopping castration prior to progression would mean that any subsequent tumour growth would be solely sustained by the proliferation of androgen-dependent stem cells • The stem cells should therefore be susceptible once again to androgen withdrawal • Thus, intermittent androgen deprivation (IAD) could delay the emergence of the androgen-independent clone • This rationale has been developed mainly through models • Shionoggi mouse by Akakura • With a possible better result • But it may be significantly different to tumour behaviour in men • Other possible benefits of IAD include the preservation of QoL in off treatment period, possible long-term benefits include bone protection and/or a protective effect against the metabolic syndrome • A reduction in treatment cost Intermittent hormone therapy: Not a standard for many urologists and oncologists. Why? Presented F.Calais Da Silva, Lisbon (PT) at ESOU16 15-17 Jan 2016

  14. PSA anxiety • Medical • Patient • Lack of information • No change • Controversial Intermittent hormone therapy: Not a standard for many urologists and oncologists. Why? Presented F.Calais Da Silva, Lisbon (PT) at ESOU16 15-17 Jan 2016

  15. Patient population and treatment cycles in seven phase III trials on IAD Intermittent hormone therapy: Not a standard for many urologists and oncologists. Why? Presented F.Calais Da Silva, Lisbon (PT) at ESOU16 15-17 Jan 2016

  16. Oncological results in seven phase III trials on IAD Intermittent hormone therapy: Not a standard for many urologists and oncologists. Why? Presented F.Calais Da Silva, Lisbon (PT) at ESOU16 15-17 Jan 2016

  17. QoL and safety in the seven phase III trials on IAD Intermittent hormone therapy: Not a standard for many urologists and oncologists. Why? Presented F.Calais Da Silva, Lisbon (PT) at ESOU16 15-17 Jan 2016

  18. Practical aspects for IAD • All published experiences are based on complete androgen blockade (CAB), considered as standard treatment • The induction cycle must last between 3-9 months • The treatment is stopped only if patients have fulfilled all the following criteria: • Well-informed and compliant patients • No clinical progression • Clear PSA response, empirically defined as a PSA<4ng/ml in metastatic disease, or <0.5ng/ml in relapsing disease • Strict follow-up is mandatory, with clinical examination every 3-6 months • The more advanced the disease, the closer the follow-up • The same laboratory should be used to measure the PSA level Intermittent hormone therapy: Not a standard for many urologists and oncologists. Why? Presented F.Calais Da Silva, Lisbon (PT) at ESOU16 15-17 Jan 2016

  19. Treatment is resumed when the patient reaches either a clinical progression, or PSA above a predetermined, empirically fixed, threshold • Usually 4-10ng/ml in non-metastatic or 10-20ng/ml in metastatic cases. The same treatment is used for at least 3-6 months • Subsequent cycles of treatment are based on the same rules until the first sign is seen of a castrate-resistant status • The best population to consider for IAD has still to be fully characterised • However, the most important factor seems to be the patient’s response to the first cycle of IAD, the PSA level response, initial PSA • We are waiting for one randomised trial SEUG 9901 to mature to publication with 1544 patients and statistical power and QoL to give more information

  20. Conclusion • Seven extensively described phase 3 trials randomising 4675 patients to IAD vs continuous ADT • The induction periods ranged from 3 -8 months; in all but one trial, the PSA level designated for ADT discontinuation was 4ng/ml. Mean follow-up ranged from 40-108 months • Collectively, these trials support the concept that, mainly in metastatic cases, IAD can produce oncologic results similar to continuous ADT • In terms of overall survival, the hazard ratios for IAD and continuous ADT were very similar (range:0.98-1.08) • The QoL benefit of IAD appears to be modest at best • With IAD, QoL is likely influenced by the duration of the off-treatment periods and by the rate of testosterone recovery Intermittent hormone therapy: Not a standard for many urologists and oncologists. Why? Presented F.Calais Da Silva, Lisbon (PT) at ESOU16 15-17 Jan 2016

  21. Take home message • Intermittent androgen-deprivation therapy (ADT) can produce oncologic results similar (not inferior, as defined by some trials) to those of continuous ADT but with potentially better tolerability • Better stratification is needed in terms of prognostic parameters such as disease extension and Gleason score • It must be used in some patients Intermittent hormone therapy: Not a standard for many urologists and oncologists. Why? Presented F.Calais Da Silva, Lisbon (PT) at ESOU16 15-17 Jan 2016

  22. ESOU 2016: Prostate Cancer Radium 223 dichloride for metastatic CRPC: The urologist's perspective Can the Bone Tropism of Prostate Cancer be turned into an Achilles heel? P. Chlosta, Crakow (PL) Santor O AUA 2013 • Prostate cancer is the most bone tropic of the major solid tumours • Bone/soft tissue ratios are exceptionally high for metastatic prostate cancers compared to other solid tumours • More than 90% of metastatic prostate cancer patients enrolled in recent metastatic castration resistance prostate cancer (mCRPC) trials have evidence of bony spread • Can we exploit bone tropism for therapeutic benefit?

  23. Radium-223 mechanism of action From Shore ND et al Urology, 2015: 85: 717-724 Radium 223 dichloride for metastatic CRPC: The urologist’s perspective Presented P. Chlosta, Crakow (PL) at ESOU16 15-17 Jan 2016

  24. Skeletal related events (SRE) represent a dramatic evolution of bone metastatic CRPC, with an estimated OS of 7-10 months after first SRE. PCa is a biologically heterogeneous disease, so targeting osteoblasts rather than PCa cells is an appealing option • Radium-223 is a radioelement which is captured by osteoblasts and emits alpha radiation. The tissue penetration of alpha radiation is very low (<0.1 mm), thus limiting toxicity on other cells than osteoblasts • The key results come from the ALSYMPCA study Primary end point: OS Key secondary end points • Time to first symptomatic skeletal event (SSE) • Changes in the PSA and alkaline phosphatase levels • Safety • QoL assessments • SSEs composed the need to administer EBRT for bone pain • New symptomatic pathologic bone fracture (vertebral or non-vertebral) • Spinal cord compression • Tumour related orthopaedic surgical intervention Radium 223 dichloride for metastatic CRPC: The urologist’s perspective Presented P. Chlosta, Crakow (PL) at ESOU16 15-17 Jan 2016

  25. ALSYMPCA (ALpharadin in SYMptomatic Prostate Cancer) Phase 3 Study Design TREATMENT 6 injections at 4-week intervals PATIENTS STRATIFICATION • Confirmed Symptomatic CRPC • ≥2 bone metastases • No known visceral metastases • Post-docetaxel, unfit for docetaxel, or refused docetaxel • Total ALP: • < 220 U/L • vs ≥ 220U/L • Bisphosphonate • use: • Yes vs No • Prior docetaxel: • Yes vs No Radium-223 (50 kBq/kg) + Best standard of care RANDOMIZED Placebo (saline) + Best standard of care 2:1 Planned follow-up is 3 years N=921 Parker C, Nilsson S, Heinrich D and al. N Engl J Med. 2013 Jul 18;369(3):213-23 Radium 223 dichloride for metastatic CRPC: The urologist’s perspective Presented P. Chlosta, Crakow (PL) at ESOU16 15-17 Jan 2016

  26. HR = 0.695 95% CI, 0.581-0.832 p=0.00007 % Radium-223, n=614 Median OS: 14.9 months Placebo, n=307 Median OS: 11.3 months Radium 223 dichloride for metastatic CRPC: Results • OS was improved as well as the time to first SRE. Adverse effects tended to be less in the radium-223 group as compared to placebo with a modest increase in myelosuppression (thrombocytopenia) ALSYMPCA Updated Analysis Overall Survival Summary of Adverse Events Parker C at al: J Clin Oncol Abstr LBA1512 P value is for descriptive purposes only. Parker C at al: J Clin Oncol Abstr LBA1512 Radium 223 dichloride for metastatic CRPC: The urologist’s perspective Presented P. Chlosta, Crakow (PL) at ESOU16 15-17 Jan 2016

  27. ALSYMPCA Conclusions In CRPC patients with bone metastases • Only one compound, radium-223 significantly prolongs overall survival • P value = 0.00185; HR = 0.695; 95% CI, 0.552-0.875 • Radium-223 significantly prolonged time to first clinically relevant SRE • P value = 0.00046; HR = 0.610; 95% CI 0.461-0.807 • Radum-223 was very well tolerated

  28. 100 Radium-223 (n=250): 19.6 Placebo (n=124): 10.2 HR 0.49, p<0.001 Radium-223 (n=364): 11.8 Placebo (n=183): 8.4 HR 0.77, p=0.068 100 80 80 60 60 Patients Without SSE, % Patients Without SSE, % 40 40 20 20 0 0 3 4 8 12 16 20 32 24 28 3 4 8 12 16 20 32 24 28 Months Months • Interestingly, the effects of ra-223 on SRE were potentiated by bisphosphonates Radium 223 dichloride for metastatic CRPC: Combination Combine Effective Agents Time to SSE in patients With CRPC and Bone Metastases Ra 223 + bisphosphonates Ra 223 Sartor, Lancet Oncol 2014 The message was conveyed that urologists should cooperate with oncologists and become more involved in the management of new active agents in the treatment of HSPC and CRPC Radium 223 dichloride for metastatic CRPC: The urologist’s perspective Presented P. Chlosta, Crakow (PL) at ESOU16 15-17 Jan 2016

  29. Overall conclusions • Urologist can effectively manage advance prostate cancer • Radium-223 joins immunotherapy, novel hormonal agents and CHTH • Multidisciplinary coordination while monitoring patient during and after treatment • After decades of effort, a bone targeted approach has been demonstrated in phase III to prolong survival • Many new challenges exist, but how to combine effective agents for maximal benefit is one of the next clear areas of focus Radium 223 dichloride for metastatic CRPC: The urologist’s perspective Presented P. Chlosta, Crakow (PL) at ESOU16 15-17 Jan 2016

  30. Bladder Cancer

  31. BacilleCalmette-Guerin (BCG) is a well established treatment for intermediate and high risk non-muscle invasive bladder cancer In patients with high risk tumours associated to CIS in the absence of BCG it is recommended to undergo a radical cystectomy In terms of medical treatments, potential treatments are summarised BCG: an established treatment BCG is a well established treatment for intermediate and high risk non-muscle invasive bladder cancer It is not perfect, since there are recurrences and progression, but is the most effective treatment in patients with CIS and/or high grade bladder cancer ESOU 2016: Bladder Cancer Alternative adjuvant treatments for the NMIBC in the BCG shortage era J Palou, Barcelona (ES)

  32. Clinical practice recommendations for the management of non-muscle invasive bladder cancerLamm D et al Eur J Urol Suppl 7 2008 Alternative adjuvant treatments for the NMIBC in the BCG shortage era Presented J Palou, Barcelona (ES) at ESOU16 15-17 Jan 2016

  33. The problem… In July 2012: Sanofi-Pasteur announced that they were halting production of Immuncyst, the Connaught strain of BCG, after inspectors found mould in the sterile manufacturing area of their Toronto plant following a previous flood What has been the problem with such a BCG shortage? Patients are receiving and still in some countries, suboptimal courses or no BCG, that may result in higher recurrence rates and, for the very highest risk cases, higher progression rates Alternative adjuvant treatments for the NMIBC in the BCG shortage era Presented J Palou, Barcelona (ES) at ESOU16 15-17 Jan 2016

  34. Treatment options in BCG failure • Mitomycin: only 19% disease free at 3 years • Valrubicin: complete response of 21% • Interferon alfa 2b: nothing • Gemcitabine: only 50% complete response at 3 months • Docetaxel: 22% free of disease at 3 years • Paclitaxel: 50% response at 2 years DAT: Device assisted therapy • The availability of DAT is a possibility with promising results in intermediate risk, high risk and in BCG failures • Local availability of some DAT will vary from country to country and by hospital • The combination of EMDA or hyperthermia with mitomycin offer better results

  35. Alternative adjuvant treatments for the NMIBC in the BCG shortage era: Summary • Local microwave (RF) induced hyperthermia with MMC (SYNERGO, RITE) have produced promising results , but more scientific evidence is needed and there is an increase in side effects as compared to MMC alone. • Chemotherapy and intravesical hyperthermia • Systematic review: 22 studies. SYNERGO • Only 2 RCT • 59% lower recurrence with C-HT than with MMC only • 87.6% bladder preservation • Inconclusive in regards to recurrence and progression time • Indications: • High grade patients with recurrent tumours, no candidates to radical cystectomy (RC) • High risk patients with recurrence and with contraindication for BCG Alternative adjuvant treatments for the NMIBC in the BCG shortage era Presented by J. Palou, Barcelona (ES) at ESOU16 15-17 Jan 2016

  36. RITE (n=60) BCG (n=72) • There are a series of proposals, according to risk factors PP RITE and BCG RFS (=132) 100 80 p=0.0083 Proposals 60 N=190 Randomised trial 11 centres Patients Intermediate and high risk Recurrence–free survival (%) 40 20 0 0 5 10 15 20 25 Months Abstract 944, EAU Madrid 2015 Alternative adjuvant treatments for the NMIBC in the BCG shortage era Presented by J. Palou, Barcelona (ES) at ESOU16 15-17 Jan 2016

  37. Therapeutic Options in High-risk Non-muscle-invasive Bladder Cancer During the Current Worldwide Shortage of BacilleCalmette-Guerin • Hugh Mostafid, Joan Palou Redorta, Richard Sylvester, J. Alfred Witjes • 1 - No maintenance • 2 - 1/3 of the dose • 3 - IR: mitomycin + maintenance • 4 - Chemohyperthermia in high risk • 5 - Gemcitabine • 6 - Radical Cystectomy • Discussion suggested that on-going trials with PD-1/PD-L1 agents might profoundly change the landscape Alternative adjuvant treatments for the NMIBC in the BCG shortage era Presented by J. Palou, Barcelona (ES) at ESOU16 15-17 Jan 2016

  38. Conclusions • No specific treatment for NMIBC due to BCG shortage • Different variables are going to influence the final decision • The combined decision of the clinician and the patient will determine the most theoretically beneficial treatment Alternative adjuvant treatments for the NMIBC in the BCG shortage era Presented by J. Palou, Barcelona (ES) at ESOU16 15-17 Jan 2016

  39. Questions?

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