Session 4 Chemotherapy for castration refractory prostate cancer First and second- line chemotherapy

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$Session 4 Chemotherapy for castration refractory prostate$

1 Session 4 Chemotherapy for castration refractory prostate cancer First and second- line chemotherapy October ESMO

2 2004 October Fyraftensmøde 2

3 2010 October Fyraftensmøde 3

4 SWOG 9916 OS 17.5 mo vs 15.6 mo Jan Petrylak DP, Tangen CM, Hussain MH, et al:docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. Fyraftensmøde N Engl J Med 351: ,

5 TAX 327 OS: median 19.2 mo vs mo vs 16.3 (MI arm) 18.6% alive after 3 years Jan Berthold DR, Pond GR, Soban F, et al.: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated Fyraftensmøde survival in the TAX 327 study. J Clin Oncol 26: ,

6 Median survival 15.1 vs 12.7 months HR for death 0.70 (p<0.0001) Jan Fyraftensmøde 6

7 Therapies in Addition to Androgen- Deprivation Therapy: Therapies with demonstrated survival and quality- of- life benefits: Docetaxel and prednisone should be offered Benefit: moderate; harm: moderate; evidence strength: strong; recommendation strength: moderate Therapies with demonstrated survival benefit and unclear quality- of- life benefit: Cabazitaxel and prednisone may be offered to men who experience progression with docetaxel Benefit: moderate; harm: moderate to high; evidence strength: strong; recommendation strength: moderate October American Society of Clinical Oncology Clinical Practice Guideline Committee approval: April 26, 2013; ESMO 7

8 St. Gallen consensus: Docetaxel chemotherapy as first- line therapy for otherwise healthy asymptomatic/minimally symptomatic CRPC patients Yes in minority of selected patients 42% No 49%

9 St. Gallen consensus: Docetaxel chemotherapy as first- line therapy for otherwise healthy asymptomatic/minimally symptomatic CRPC patients Yes in minority of selected patients 42% No 49% Docetaxel chemotherapy as first- line therapy for symptomatic CRPC patients Yes in minority of selected patients 50% yes 41%

10 Chemotherapy Chemotherapy

11 Chemotherapy AR pathways inhibitor

12 Chemotherapy

13 AR pathways inhibitor Chemotherapy AR pathways inhibitor Chemotherapy

14 Not supported by data AR pathways inhibitor AR pathways inhibitor Chemotherapy Chemotherapy

15 Duration of response to first ADT and efficacy of subsequent endocrine therapy and docetaxel in mcrpc 100% PSA response > 30% with first and subsequent ADT 80% PSA response > 30% with docetaxel 75% 60% 50% <12 mo >12 40% mo 25% 20% 0% First ADT Subsequent ADT 0% Response to ADT <12 mo 153 patients with mcrpc Angelergues A et al. ASCO 2014

16 Short response to ADT limited evidence that October ESMO 16

17 St. Gallen consensus: Healthy symptomatic patient with a short- response ( 12 months) to primary ADT - Docetaxel as first- line therapy? Yes 57% Yes in minority of selected patients 41% Short- response to primary ADT, but asymptomatic or minimally symptomatic - Docetaxel as first- line therapy? No 21% yes in minority of selected patients 49%

18 Gleason and docetaxel TAX 327 October ESMO 18 Robert J. van Soest et al. Eur Urol in press

19 Gleason and cabazitaxel Forty- seven patients Patients received a median of nine cycles of cabazitaxel. Median progression- free survival was 7.0 months (95% CI: ). At multivariate analysis, a higher Gleason score ( 8) appeared to be associated with prolonged progression- free survival (hazard ratio: 0.36; 95% CI: ); the higher Gleason score showed no statistical impact on overall survival. October ESMO Buonerba C et al. Future Oncol Jun: 9:

20 Short response to ADT limited evidence that patients with <16 months response to initial androgen- deprivation therapy (ADT) may respond aggressive better to disease chemotherapy than subsequent Gleason score hormone 8 are therapies often considered candidates for chemotherapy, although October definitive data supporting this ESMO 20

21 Survival according to metastatic side TAX 327 liver metastases with or without other metastases median OS (10.0 months) lung metastases with or without bone or lymph node metastases (median OS 14.4 months), bone plus lymph node metastases (median OS 15.7 months), bone- only metastases (median OS 19.0 months), lymph node- only metastases (median OS 26.7 months) October ESMO 21

22 Short response to ADT limited evidence that patients with <16 months response to initial androgen- deprivation therapy (ADT) may respond better to chemotherapy than subsequent hormone therapies aggressive disease Gleason score 8 and visceral metastases are often considered candidates for chemotherapy, although definitive data supporting this approach do not exist Visceral metastases no comparative studies of chemotherapy and AR- targeting agents visceral metastases were an exclusion criterion for studies evaluating sipuleucel- T, abiraterone acetate plus October ESMO 22

23 Number of treatment cycles October ESMO 23 Armstrong AJ et al. Clin Cancer Res 2010,16,

24 Optimal duration Number of cycles No survival benefit of more than 10 cycles October ESMO Pond et al. Eur Urol 2012,61,

25 Treatment related to age All patients Age 68 years Age 69 years No pain Pain KPS 80% KPS 90% FACT-P <109 FACT-P 109 No visceral disease Visceral disease PSA <115 ng/ml PSA 115 ng/ml Favors Docetaxel q3w Favors Mitoxantrone October ESMO 25 Berthold Berthold D et D al. et J. al. Clin. J. Clin. Oncol. Oncol. 2008; 2008; 26: :242-45

26 First- line docetaxel- based chemotherapy in CRPC patients aged >75 yr. Age by itself should not be used as a criterion to deny patients with CRPC a potentially effective chemotherapy. October Italiano A ESMO et al. European urology 55 ( )

27 Not everybody receives chemotherapy % of cohort % receiving chem 18 0 < 70 years years > 80 years Lissbrant IF et al. Acta Oncol 2013;52:

28 AR- V7- positive patients: do they retain sensitivity to taxane CTCs for AR- V7 mrna were examined Of 37 taxane- treated patients enrolled, 17 (46%) had detectable AR- V7 in CTCs PSA responses were achieved in both AR- V7- positive and AR- V7- negative men (41% vs 65%; P =.19) Detection of AR- V7 in CTCs from men with metastatic CRPC is not associated with primary resistance to taxane chemotherapy Antonarakis ES et al. JAMA Oncol Jun 4. doi: [Epub ahead of print],

have agents clinical implications between androgen- when combining

29 Cross- resistance cross resistance can occur between different taxanes between taxanes and androgen- targeting Cross resistance have agents clinical implications between androgen- when combining and targeting agents sequencing these drugs Oct- 15 ESMO preceptorship 29

30 Enzalutamide naive vs enzalutamide- resistant tumors Van Soest et al. Eur Urol xxx2014

31 To evaluate the antitumour activity of cabazitaxel in mcrpc pretreated with abiraterone or enzalutamide. Changes in prostate- specific antigen (PSA) levels and progression- free survival were used to determine the activity of cabazitaxel treatment. A total of 79 patients who had progressive mcrpc after docetaxel (median: 8 cycles; range: 4 12 mo), and AA (median: 4.8 mo; range:1 55 mo) received cabazitaxel 25 mg/m2 every 3 weeks (median: 6 cycles; range:1 15 cycles).

32 62% 35% Nakousi et al. Eur Urol xxx2014

33 Response to cabazitaxel after abiraterone and/or enzalutamide Pezaro et al. Eur Urol 2014

34 Post hoc analysis order abiraterone- cabazitaxel cab- abi October No significant diff. in OS, but in PFS Cab Abi treated patients: 8.1 months Abi Cab treated tumor response patients: of 6.5 both months agents, particularl y cabazita xel, was lower when administe red as Retrospective analysis of cabazitaxel and abiraterone 63 patients received Cab Abi (cabazitaxel prior to abiraterone) and 69 patients received Abi Cab Int J Cancer Sep 20 ESMO 34

35 Statement: Retrospective data demonstrate benefit of docetaxel following abiraterone in chemotherapy- naïve patients and cabazitaxel following AR targetet therapy in chemotherapy exposed patients Cabazitaxel and AR- pathway inhibitors are not cross- resistant. Preclinical data suggest that cabazitaxel activity does not act mainly through AR axis inhibition No study of high level of evidence is available to support any recommendation on sequential treatment for mcrpc. There are only clues that prospective clinical studies need to confirm.

36 Recommandation!

37 Supported by phase III data

38 TREATMENT CHALLENGES: AR- NEGATIVE/ NEUROENDOCRINE PROSTATE CANCER Characteristics Aggressive, treatment- resistant variant Reduction or loss of AR signaling High risk, poor prognosis Presentation with symptomatic, visceral disease common Treatment High likelihood of primary resistance to AR targeted treatment therapy, Probable response to chemotherapy First- and second- line platinum- based chemotherapy Combinations show initial but not durable activity Studies to identify and test new molecular targets underway

39 What happens when early chemotherapy becomes an option?

SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract on Prostate Cancer) In Oncologia

SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract on Prostate Cancer) In Oncologia Divisione di Oncologia Medica Unità Tumori Genitourinari SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract