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

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

3. Sequential therapies in metastatic PCa Enrico Cortesi The standard of care for CRPC changed from mitoxantrone/prednisone to docetaxel/prednisone based on TAX-327 and SWOG 99-16 studies [1,2] SWOG 99-16: Docetaxel/estramustine improved median survival by 2 mos vs mitoxantrone/prednisone [2] TAX-327: Docetaxel improved survival and rates of response in terms of pain, PSA level, and quality of life vs mitoxantrone/prednisone [1] 1. Tannock TF, et al. N Engl J Med. 2004;351:1502-1512. 2. Petrylak DP, et al. N Engl J Med. 2004;351:1513-1520. 100 80 60 40 20 0 OS (%) Mos 33036912182124273015 Docetaxel q3w Weekly docetaxel Mitoxantrone 100 80 60 40 20 0 OS (%) P =.02 Mos 480123624 Docetaxel + estramustine (217 deaths; median: 17.5 mos) Mitoxantrone + prednisone (235 deaths; median: 15.6 mos) Docetaxel First to improve OS

4. Sequential therapies in metastatic PCa Enrico Cortesi Docetaxel First to improve OS As consequence of OS advantage reported in 2004, threes spaces emerged for CRPC with new end-point for treatment of CRPC Pre-docetaxel asymptomatic or mildly symptomatic DocetaxelPost docetaxel To delay symptoms and CHT beginning To improve OS and efficacy of TXT To improve OS and disease control.

5. Sequential therapies in metastatic PCa Enrico Cortesi From Oliver Sartor ASCO 2012 Educational Session

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

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

8. Sequential therapies in metastatic PCa Enrico Cortesi 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.

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

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

11. Sequential therapies in metastatic PCa Enrico Cortesi Difference in patient populations in APC phase III trials The reason why thesestudies are not comparable! CabaAbiMDV3100Alph Age6869 70 ECOG ≤193%90%91.2%86% mPSA (ng/ml)143.9198.8107.7159 Bone disease80%89%91.3%100% Soft Tiss dis25%/70.9%0% Liver dis/11%11.6%0% Only 1 prev therapy 69%70%72.4%/ PD TXT < 3m last dose 48%/

12. Sequential therapies in metastatic PCa Enrico Cortesi 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.

13. Sequential therapies in metastatic PCa Enrico Cortesi 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.

14. Denosumab and Continous Care in PCa. Enrico Cortesi Time of M0 to M1 and Death in Progressive, Nonmetastatic CRPC Time to Bone MetastasisTime to Death 25 mos46.8 mos Smith MR, et al. Cancer. 2011;117:2077-2085. Mos Since Randomization 6304866 0 0.2 0.4 0.6 0.8 Probability of Bone Metastases 0 0.1 0.3 0.5 0.7 0.9 1.0 12182436426054 Cumulative incidence function 95% CI Mos Since Randomization 6304866 0 0.2 0.4 0.6 0.8 Probability of Death 0 0.1 0.3 0.5 0.7 0.9 1.0 12182436426054 Kaplan-Meier estimate 95% CI

15. Denosumab and Continous Care in PCa. Enrico Cortesi Timing of Disease Progression in Prostate Cancer  Castration-Resistant Prostate Cancer M0M1 AsymptomaticM1 Symptomatic M0 M1 M1+ A continuum, but not equal in time 25-30 10-12 10-15 Mos

16. Sequential therapies in metastatic PCa Enrico Cortesi Bone Health in Prostate cancer: Skeletal Complications Negative impact on survival [5] Men with prostate cancer without skeletal fracture survived 39 mos longer than those with a fracture Increased medical costs [1] Treatment of bone complications more than doubles the total treatment costs for patients with bone metastases Impaired mobility [6] Hip fracture associated with a 50% long- term disability rate; 25% require nursing home care Diminished quality of life [2-4] History of a skeletal complication is associated with lower QoL in breast and prostate cancer 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.

17. Sequential therapies in metastatic PCa Enrico Cortesi 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 SRE and Quality of Life (QoL)

18. Sequential therapies in metastatic PCa Enrico Cortesi 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

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

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

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

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

23. Sequential therapies in metastatic PCa Enrico Cortesi Bone Health in Prostate cancer:

24. Sequential therapies in metastatic PCa Enrico Cortesi Bone Health in Prostate cancer:

25. Sequential therapies in metastatic PCa Enrico Cortesi 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.

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

27. Sequential therapies in metastatic PCa Enrico Cortesi 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.

28. Sequential therapies in metastatic PCa Enrico Cortesi 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

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

30. Sequential therapies in metastatic PCa Enrico Cortesi 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 Only Bone mts Alpharadin + Denosumab or Zometa Yes At least 3 months of TXT No

31. Sequential therapies in metastatic PCa Enrico Cortesi 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.

32. Sequential therapies in metastatic PCa Enrico Cortesi 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

33. Sequential therapies in metastatic PCa Enrico Cortesi … then we have not evidence to treat patients with ECOG-PS=2, but… How many are these patients? pts ECOG-PS=2 Caba vs Mtx8% Abi vs Pbo10% MDV3100 vs Pbo8% Alph vs Pbo13% Recently we presented a meta- analysis at SIURO 2012 that reports that also these patients achieved a benefit from treatment. Probably, in real world the number of these patient is greater! 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

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

35. Sequential therapies in metastatic PCa Enrico Cortesi 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.

36. Sequential therapies in metastatic PCa Enrico Cortesi “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 …

37. Sequential therapies in metastatic PCa Enrico Cortesi 100 80 60 40 20 0 0 Progression-Free (%) 369151812 546 542 489 400 340 204 164 90 12 3 0000 AA PL 46 30 Time to Progression or Death (Months) AA + P PL + P “The risk to be refractory to treatment”: The risk to be refractory to abiraterone in CRPC CHT naïve is less than 10%! <10% CRPC CHT naive 35% CRPC CHT treated Factor which increase resistance …probably resistance to therapy is not influenced by the type of therapy but by several molecular pathways that need to be investigated!

38. Sequential therapies in metastatic PCa Enrico Cortesi 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.

39. Sequential therapies in metastatic PCa Enrico Cortesi How to choose a sequential therapy? New evidences may help the clinicians! 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 60 40 20 0 0 Progression-Free (%) 369151812 546 542 489 400 340 204 164 90 12 3 0000 AA PL 46 30 Time to Progression or Death (Months) AA + P PL + P 546 542 538 534 482 465 452 437 27 25 0000 524 509 503 493 0202 120 106 258 237 412 387 100 80 60 40 20 0 0 Survival (%) 3121527 Time to Death (Months) 33 AA + P PL + P 6930242118 AA PL AA + P (median, mos):NR PL + P (median, mos):27.2 HR (95% CI):0.75 (0.61-0.93) P value:0.0097 AA + P (median, mos):NR PL + P (median, mos):8.3 HR (95% CI):0.43 (0.35-0.52) P value:< 0.0001 PFS 0S

40. Sequential therapies in metastatic PCa Enrico Cortesi 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…

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

42. Sequential therapies in metastatic PCa Enrico Cortesi CRPC treated with TXT Only Bone mts Alpharadin + Denosumab or Zometa Yes At least 3 months of TXT No A possible algorithm: CabazitaxelAbirateroneMDV3100 Chose what you want but use it well… docetaxel included! PS=2 Yes No Hormonal therapies Yes