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How should we sequence therapy?

New Perspectives in Metastatic Prostate Cancer . How should we sequence therapy?. Enrico Cortesi Roberto Iacovelli. Dipartimento Scienze Radiologiche , Oncologiche e Anatomo Patologiche ; Oncologia B. “ Sapienza” Università di Roma. Natural History of Prostate Cancer.

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How should we sequence therapy?

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  1. New Perspectives in Metastatic Prostate Cancer  How should we sequence therapy? Enrico Cortesi Roberto Iacovelli • DipartimentoScienzeRadiologiche, Oncologiche e AnatomoPatologiche; Oncologia B. • “Sapienza” Universitàdi Roma

  2. Natural History of Prostate Cancer • Typical patient presentation as they move through different stages Under UROLOGIST care Under the care of ONCOLOGIST Under ONCOLOGIST care Androgen deprivation First-line therapy Therapies after LHRH agonists and antiandrogens Death Local therapy Salvage therapy Burden of disease Symptomatic Asymptomatic Nonmetastatic Metastatic Castrate sensitive Castrate resistant Higano C, et al. In: Figg WD, et al. Drug management of prostate cancer; 2010. Denosumab and Continous Care in PCa. Enrico Cortesi

  3. From Oliver Sartor ASCO 2012 Educational Session Sequential therapies in metastatic PCa EnricoCortesi

  4. How many patients have 2nd line? mPCa 100% of pts (…I hope!) ADT 50-60% of pts1 Docetaxel 25% of pts2 …It’s reductive ,I know, but now the hot question is: “what is the best second line?” 2nd line 1- Ryan et al. ASCO 2012; 2-Berthold et al. Ann Oncol. 2008 Oct;19(10):1749-53. Sequential therapies in metastatic PCa EnricoCortesi

  5. Why a sequential therapy? In few years 4 studies reported a significant improvement of OS in CRPC patients after docetaxel failure. Cabazitaxel* 15.1 Cabazitaxel* 6.4 Mitoxantrone* 12.7 Mitoxantrone* 3.1 Abiraterone* 14.8 Abiraterone* 10.2 Placebo* 10.9 Placebo* 6.6 MDV3100 18.4 MDV3100 8.3 Placebo 13.6 Placebo 2.9 Alpharadin 14.0 PSA-PFS Placebo 11.2 * Plus Prednisone Overall Survival Sequential therapies in metastatic PCa EnricoCortesi

  6. How to choose a sequential therapy? • Several considerations: • Patient progressed to docetaxel have a median survival from 11 to 13.5 mos • The median improvement in OS with new agents is 3-5 mos • CHT is confirmed to be effective in CRPC • Hormonal Therapy is confirmed to be effective in CRPC • Patients with good PS ask for more treatment • Tumor related symptoms must be palliate, when possible, with active drugs. Sequential therapies in metastatic PCa EnricoCortesi

  7. How to choose a sequential therapy? Patients with visceral mets: + + MDV3100 OS=18.4 Cabazitaxel PFS=6.4 Abiraterone PFS=10.2 Increase of OS of 16 mos!! This would be great but is not EBM!!!! Patients with bone mets only: + + + Alpharadin OS=14.0 MDV3100 PFS=8.3 Abiraterone PFS=10.2 Cabazitaxel PFS=6.4 Increase of OS of 24 mos!! Sequential therapies in metastatic PCa EnricoCortesi

  8. How to choose a sequential therapy? Why trials are not comparable! Cabazitaxel 6.4 Mitoxantrone 3.1 Mitoxantrone and placebo are longer considered equally and placebo PSA-PFS showed greater variability! Abiraterone 10.2 Placebo 6.6 MDV3100 8.3 patients selection might make a difference!!! Placebo 2.9 PSA-PFS Sequential therapies in metastatic PCa EnricoCortesi

  9. Difference in patient populations in APC phase III trials The reason why thesestudies are not comparable! Sequential therapies in metastatic PCa EnricoCortesi

  10. How to choose a sequential therapy? • Factors to be considered for a second line therapy after docetaxel failure: • Type of disease: bone only vs. visceral; • Time to PD after docetaxel discontinuation; • Total dose of docetaxel received; • Patient clinical status and PS • Risk to resistance to therapy. Sequential therapies in metastatic PCa EnricoCortesi

  11. How to choose a sequential therapy? • Factors to be considered for a second line therapy after docetaxel failure: • Type of disease: bone only vs. visceral; • Time to PD after docetaxel discontinuation; • Total dose of docetaxel received; • Patient clinical status and PS • Risk to resistance to therapy. Sequential therapies in metastatic PCa EnricoCortesi

  12. Time of M0 to M1 and Death in Progressive, Nonmetastatic CRPC Time to Bone Metastasis Time to Death 1.0 1.0 Cumulative incidence function Kaplan-Meier estimate 0.9 0.9 95% CI 95% CI 0.8 0.8 0.7 0.7 0.6 0.6 Probability of Bone Metastases Probability of Death 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 25 mos 46.8 mos 0 0 0 6 12 18 24 30 36 42 48 54 60 66 0 6 12 18 24 30 36 42 48 54 60 66 Mos Since Randomization Mos Since Randomization Smith MR, et al. Cancer. 2011;117:2077-2085. Denosumab and Continous Care in PCa. Enrico Cortesi

  13. Timing of Disease Progression in Prostate Cancer Castration-Resistant Prostate Cancer M0 M1 Asymptomatic M1 Symptomatic A continuum, but not equal in time M1 M0 M1+ 25-3010-1210-15 Mos Denosumab and Continous Care in PCa. Enrico Cortesi

  14. Bone Health in Prostate cancer: Increased medical costs[1] Treatment of bone complications more than doubles the total treatment costs for patients with bone metastases Diminished quality of life[2-4] History of a skeletal complication is associated with lower QoL in breast and prostate cancer Impaired mobility[6] Hip fracture associated with a 50% long-term disability rate; 25% require nursing home care Skeletal Complications Negative impact on survival[5] Men with prostate cancer without skeletal fracture survived 39 mos longer than those with a fracture 1. Groot MT, et al. Eur Urol. 2003;43:226-232. 2. Weinfurt KP, et al. Ann Oncol. 2005;16:579-584.3. Weinfurt KP, et al. Med Care. 2004;42:164-175. 4. Saad F, et al. Eur Urol. 2004;46:731-740. 5. Oefelein MG, et al. J Urol. 2002;168:1005-1007. 6. Riggs BL, et al. Bone. 1995;17:505S-511S. Sequential therapies in metastatic PCa EnricoCortesi

  15. SRE and Quality of Life (QoL) Changes in Functional Assessment of Cancer Therapy-General (FACT-G) scores indicate that skeletal complications reduce health-related quality of life in patients with prostate cancer. Weinfurt et al. Ann Oncol 2005 Sequential therapies in metastatic PCa EnricoCortesi

  16. Reduction of SRE is an assets in activity of new molecules for PCa Abiraterone Acetate vs. Placebo • Reduce the time to SRE of 25% of the patients having a skeletal event (9.9 vs. 4.9 months) • Reduce the rate of pain palliation among patients with a baseline pain score of 4 or more and at least one post-baseline pain score (44% vs. 27%, P = 0.002). Cabazitaxel vs. Mitoxantrone Pain response rates were similar in the two groups; there was no significant difference between the treatment groups in time to pain progression. Enzalutamide (MDV3100) vs. Placebo Reduce the risk of first skeletal event of 38%; Increase the time to first skeletal event from 13.3 to 16.7 months Sequential therapies in metastatic PCa EnricoCortesi

  17. Bone Health in Prostate cancer: Sequential therapies in metastatic PCa EnricoCortesi

  18. Bone Health in Prostate cancer: Sequential therapies in metastatic PCa EnricoCortesi

  19. Bone Health in Prostate cancer: Sequential therapies in metastatic PCa EnricoCortesi

  20. Bone Health in Prostate cancer: Sequential therapies in metastatic PCa EnricoCortesi

  21. Bone Health in Prostate cancer: Sequential therapies in metastatic PCa EnricoCortesi

  22. Bone Health in Prostate cancer: Sequential therapies in metastatic PCa EnricoCortesi

  23. Bone Health in Prostate cancer: Alpharadin reported increase of OS and TTSF in patients treated or unfit for docetaxel with exclusive bone disease. Treatment with other agents which prevent SREs is feasible. This treatment should be considered the first option in patients without visceral disease. Simultaneous treatment with other antineoplastic agents (specially hormonal agents) may be feasible due to the low toxicity. Sequential therapies in metastatic PCa EnricoCortesi

  24. A possible algorithm: CRPC treated with TXT Yes Only Bone mts Alpharadin + Zometa or Denosumab Sequential therapies in metastatic PCa EnricoCortesi

  25. How to choose a sequential therapy? • Factors to be considered for a second line therapy after docetaxel failure: • Type of disease: bone only vs. visceral; • Time to PD after docetaxel discontinuation; • Total dose of docetaxel received; • Patient clinical status and PS • Risk to resistance to therapy. Sequential therapies in metastatic PCa EnricoCortesi

  26. Time to PD to previous TXT: Cabazitaxel • CABA seems to be more active in: • patients who progress rapidly after TXT discontinuation and • received at least 3 cycles of TXT. Bono et al. Lancet 2010; 376: 1147–54 Sequential therapies in metastatic PCa EnricoCortesi

  27. Time to PD to previous TXT: Abiraterone Abiraterone is equally effective in patients progressed before or after 3 months from last dose of TXT Abiraterone seems to act better in patients exposed to docetaxel for at least 3 months Sequential therapies in metastatic PCa EnricoCortesi

  28. Time to PD to previous TXT: • Retrospective analyses of abiraterone and cabazitaxel phase III trials showed as: • The time from last dose of docetaxel to PD is not a selection criteria • Cabazitaxel and abiraterone are more effective in patients who receive correct treatment with docetaxel (at least 3 month). CRPC treated with TXT Yes No Only Bone mts Alpharadin + Denosumab or Zometa No At least 3 months of TXT Sequential therapies in metastatic PCa EnricoCortesi

  29. How to choose a sequential therapy? • Factors to be considered for a second line therapy after docetaxel failure: • Type of disease: bone only vs. visceral; • Time to PD after docetaxel discontinuation; • Total dose of docetaxel received; • Patient clinical status and PS • Risk to resistance to therapy. Sequential therapies in metastatic PCa EnricoCortesi

  30. Patient PS: Most of patients enrolled in phase III trials are ECOG-PS = 0-1, no benefit was reported in patients with PS = 2. MDV 3100 Caba Abi Sequential therapies in metastatic PCa EnricoCortesi

  31. … then we have not evidence to treat patients with ECOG-PS=2, but… How many are these patients? Probably, in real world the number of these patient is greater! Recently we presented a meta-analysis at SIURO 2012 that reports that also these patients achieved a benefit from treatment. In the overall cohort treatment reduce the risk of death of 25% (HR 0.758; 95% CI 0.574-0.999, p=0.049). The benefit was greater for patients treated with hormonal therapies compared to CHT (HR 0.74 vs 0.81) even if not significant. Altavilla, Iacovelli , Cortesi, et al. Oral presentation at SIURO2012 Sequential therapies in metastatic PCa EnricoCortesi

  32. A possible algorithm: CRPC treated with TXT Yes No Only Bone mts Alpharadin + Denosumab or Zometa No At least 3 months of TXT Yes Yes Hormonal therapies PS=2 Sequential therapies in metastatic PCa EnricoCortesi

  33. How to choose a sequential therapy? • Factors to be considered for a second line therapy after docetaxel failure: • Type of disease: bone only vs. visceral; • Time to PD after docetaxel discontinuation; • Total dose of docetaxel received; • Patient clinical status and PS • Risk to resistance to therapy. Sequential therapies in metastatic PCa EnricoCortesi

  34. “The risk to be refractory to treatment”: 62% of patients had PD as best response a 3 mos with Cabazitaxel. 35% of patients had PD as best response a 3 mos with Abiraterone. Abiraterone indirectly reduce the risk of PD as best response but … Sequential therapies in metastatic PCa EnricoCortesi

  35. “The risk to be refractory to treatment”: 100 80 The risk to be refractory to abiraterone in CRPC CHT naïve is less than 10%! 60 Progression-Free (%) 40 20 <10% CRPC CHT naive AA + P PL + P Factor which increase resistance 0 3 6 9 12 15 18 0 …probably resistance to therapy is not influenced by the type of therapy but by several molecular pathways that need to be investigated! Time to Progression or Death (Months) 35% CRPC CHT treated AA PL 546 542 489 400 340 204 164 90 46 30 12 3 0 0 Sequential therapies in metastatic PCa EnricoCortesi

  36. How to choose a sequential therapy? • PS • Is not an exclusion criteria: PS2 had the probability of 25% the risk of death if treated but no evidence are available as far as the best second line. • Type of disease bone vs. visceral • Patients with bone mets should be first treated with Alpharadin. NO head to head trials are available with other agents but this may consent to have a possibility for further bone or visceral progression. • Time to PD after docetaxel discontinuation • Available evidences do not showed a benefit for abiraterone or cabazitaxel based on time from last dose of docetaxel to PD. • Total dose of docetaxel received; • The availability of “second lines” is not a criteria to avoid treatment with docetaxel. Sequential therapies in metastatic PCa EnricoCortesi

  37. How to choose a sequential therapy? New evidences may help the clinicians! 100 Interim Analysis Results of COU-AA-302, a Randomized, Phase 3 Study of Abiraterone Acetate (AA) in Chemotherapy-Naïve Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC) 100 80 80 60 Survival (%) 0S PFS 60 Progression-Free (%) 40 40 20 AA + P PL + P 20 AA + P PL + P 0 3 6 9 12 15 18 21 24 27 30 33 0 0 Time to Death (Months) 3 6 9 12 15 18 0 546 542 538 534 524 509 503 493 482 465 452 437 412 387 258 237 120 106 27 25 0 2 0 0 AA PL Time to Progression or Death (Months) AA PL 546 542 489 400 340 204 164 90 46 30 12 3 0 0 Sequential therapies in metastatic PCa EnricoCortesi

  38. How to choose a sequential therapy? New evidences may help the clinicians …or not! The correct position for abiraterone will be in chemotherapy naïve CRPC, in next future …. MDV3100 and Cabazitaxel will not be the only second lines available, new agents are in advanced phase of study: TAK700, cabozatinib, ipilimumab, etc… We will now need more comparative studies better thantrials for new agents. Meanwhile… Sequential therapies in metastatic PCa EnricoCortesi

  39. How to choose a sequential therapy? Patients with visceral mets: + + MDV3100 OS=18.4 Cabazitaxel PFS=6.4 Abiraterone PFS=10.2 Increase of OS of 16 mos!! This would be great and might make sense …. Patients with bone mets only: + + + Alpharadin OS=14.0 MDV3100 PFS=8.3 Abiraterone PFS=10.2 Cabazitaxel PFS=6.4 Increase of OS of 24 mos!! Sequential therapies in metastatic PCa EnricoCortesi

  40. A possible algorithm: CRPC treated with TXT Yes No Only Bone mts Alpharadin + Denosumab or Zometa No At least 3 months of TXT Yes Yes Hormonal therapies PS=2 No Chose what you want but use it well… docetaxel included! Cabazitaxel Abiraterone MDV3100 Sequential therapies in metastatic PCa EnricoCortesi

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