Diapositiva 1

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Taxanes and New hormonal agents How they work?
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Taxanes
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Microtubules are highly dynamic cytoskeletal
fibres that are composed of tubulin of which are
crucial to mitosis and cell division.
Jordan Nat Rev Cancer 2004
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Microtubules functions

• Cell shape
• Transport of vesicles
• Mitochondrial function
• Cell signalling
• Cell division and mitosis

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Emerging mechanistic scenarios of the effects of
taxane-based chemotherapy on microtubules and
androgen receptor signaling.
Mistry S J , and Oh W K Mol Cancer Ther
201312555-566
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Abiraterone acetate
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17? hydroxylase - 17-20 lyase
Agarwal Fut Oncol 2010 modified
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enzalutamide
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Testosterone AR Their role in PC
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Logothetis Cancer Disc 2013
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taxanes
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Seruga Nat Rev Clin Oncol 2011
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ES Antonarakis Oral presentation June 1, 2014
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ES Antonarakis Oral presentation June 1, 2014
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A Azad Poster Highlights sessione May 30, 2014
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• ARv7, which lacks the hinge region, did not
  co-sediment with microtubules, unlike ARv567.
• Nuclear accumulation and transcriptional activity
  of ARv7 was unaffected by taxane treatment.
• The microtubule-interacting splice variant ARv567
  was sensitive to taxane-induced microtubule
  stabilization.
• In ARv567-expressing LuCap86.2 tumor xenografts,
  docetaxel treatment was highly efficacious,
  whereas ARv7-expressing LuCap23.1 tumor
  xenografts displayed docetaxel resistance.

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chaarted
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C. Sweeney Abs LBA2 Plenary session June 1, 2014
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C. Sweeney Abs LBA2 Plenary session June 1, 2014
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Chemotherapy in hormone-sensitive PC

• Issues
• Rationale
• Selection criteria
• Side effects
• Magnitude of the results
• Additional data

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C. Sweeney Abs LBA2 Plenary session June 1, 2014
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Selection criteria?

• Breast cancer

• Prostate cancer

• ER/PGR pos vs neg
• Clinical/biological criteria (St.Gallen
  guidelines)
• Ki67
• HER2 status
• ER status
• PGR status
• Luminal A B
• HER2 overexpression
• Basal-like

• DRE
• GS
• PSA

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CHAARTED definition of the risk

• High volume
• Visceral mets and/or
• 4 bone mets (at last 1 beyond pelvis and
  vertebral column)

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CHAARTED definition of the risk

• High volume
• Visceral mets and/or
• 4 bone mets (at last 1 beyond pelvis and
  vertebral column)

MJ Morris Discussant Plenary session June 1, 2014
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Side effects
CHAARTED
Anemia 1
Thrombocytopenia -
Neutropenia 12
Febrile neutropenia 6
Fatigue 4
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Side effects
CHAARTED TAX 327
Anemia 1 5
Thrombocytopenia - 1
Neutropenia 12 32
Febrile neutropenia 6 3
Fatigue 4 5
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• Will chemo became the new standard for
  hormonosensitive PC pts?
• YES (for a quote of ptswaiting more accurate
  selection criteria)
• Are the presented data enough?
• NO (additional analyses are needed)

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Chemo in early stages
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Neo-adjuvant (surgery)
down organ confined mar gin -
author year Drug GS PSA T T PSA mFU RFb
Pettaway 2000 KETDOX/VBLE TAB (duration 12 wks) gt8 gt10 3 33 NR NR 33 83 13 69
Clark 2001 VP16E x 21 d/ 4 w x 3 gt8 gt15 2B-3 18 94 100 31 78 14 88
Hussain 2003 DOC/3w E 280 TID x 3-6 gt8 gt15 gt2b 21 100 100 30 (10) 70 13 71
Dreicer 2004 DOC w x 6 gt8 gt15 2b-3 29 NR 79 11 50 23 71
Beer 2004 DOCMITOX w x 4 (phase I) gt 43 gt15 2c-3a 21 NR 20/21 76 NR NR
Konety 2004 Carbo AUC 6 PCT 180 mg/sqm EMP 280 TID LHRH-A x 4-6 gt8 gt20 3-4 36 22 100 36 NR 29 55
Febbo 2005 DOC w x 24 ? 43 gt20 3 19 89 (? MRI) 58 38 NR NR NR
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Neo-adjuvant (XRT)
author year Drug GS PSA T mFU RFb
Ben Josef 2001 VP16E x 2 ? XRT E gt7 gt15 1-2 18 73 (3y DFS)
Hussain 11 XRT 2003 DOC/3w E 280 TID x 3-6 gt8 gt15 gt2b 21 13 71 (2 HT)
Zelefsky 2004 VBLE x 2? XRT VBLE x 1 gt8 gt20 gt3 27 66(5y)
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Adjuvant

• Pilepich RTOG 81-12 (Am J Clin Oncol 1986)
• XRT (64.8-70.2 Gy) ? CTXDOXCDDP
• Schmidt (Eur Urol 1996)
• XRT or surgery

• E 600 mg/sqm/d x 2 years
• CTX 1 g/sqm/3w x 2 years
• observation

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CALGB 90203 neo adj Phase III Study of Radical Prostatectomy Alone Versus Neoadjuvant Docetaxel in High Risk Localized Prostate Cancer
RTOG 9902 adj Phase III randomized study of androgen suppression and radiotherapy with or without subsequent paclitaxel, estramustine, and etoposide in patients with localized high-risk prostate cancer
SWOG 9921 adj Adjuvant Androgen Deprivation Versus Mitoxantrone Plus Prednisone Plus Androgen Deprivation in Selected High Risk Prostate Cancer Patients Following Radical Prostatectomy Phase III
XRP6976J/3501 adj A Multicenter, Open-Label, Randomized, Phase III Trial Comparing Immediate Adjuvant Hormonal Therapy (ELIGARD- leuprolide acetate) in Combination with TAXOTERE Administered Every Three Weeks Versus Hormonal Therapy Alone Versus Deferred Therapy Followed by the Same Therapeutic Options in Patients at High Risk of Relapse After Radical Prostatectomy
FRE-FNCLCC-GETUG-12/0203 neo adj Phase III randomized study of neoadjuvant releasing factor agonist therapy and antiandrogen therapy with or without docetaxel and estramustine in patients with locally advanced prostate cancer or with a high risk of relapse
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• Given the lack of phase III trials, there is
  limited data regarding the role of (neo) adjuvant
  chemotherapy with or without ADT prior to RP in
  localized or locally advanced prostate cancer

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K Fizazi Oral presentation June 1, 2014
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K Fizazi Oral presentation June 1, 2014
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K Fizazi Oral presentation June 1, 2014
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K Fizazi Oral presentation June 1, 2014
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