"Sind Bisphosphonate (und Denosumab) Standardtherapien bei der adjuvanten Behandlung von Patientinnen mit Mammakarzinom?"

Transkript

1 "Sind Bisphosphonate (und Denosumab) Standardtherapien bei der adjuvanten Behandlung von Patientinnen mit Mammakarzinom?" Monica Castiglione Genève/Zürich

2 Diskussionspunkte Anti-Tumor Wirkung der Bisphosphonate (Denosumab)? Welche Daten stehen für den adjuvanten Einsatz zur Verfügung? Sind alle Bisphosphonate gleich? Nebenwirkungen der Bisphosphonate Schlussfolgerungen (wenn möglich...)

3 Anti-Tumor Wirkung der Bisphosphonate (Denosumab)?

4 The Vicious Cycle of Bone Metastasis Tumor cells produce factors that stimulate osteoblasts to secrete RANKL Tumor-derived osteoclast activating factors Parathyroid hormone related protein Interleukin-6, -8, -11 Tumor necrosis factor Macrophage colony stimulating factor Osteoclast Tumor Cells in Bone (+) (+) Bone resorption releases growth factors from the bone matrix that may perpetuate tumor activity Bone-derived tumor growth factors Transforming growth factor-β Insulinlike growth factors Fibroblast growth factors Platelet-derived growth factor Bone morphogenic proteins Osteoblasts and other bone cells increase expression of RANKL Overexpression of RANKL drives increased formation, function and survival of osteoclasts, leading to excessive bone resorption Bone Adapted from Roodman GD. N Engl J Med. 2004;350:

5 Praeklinische Daten Zoledronic acid may work through several mechanisms, including alteration of osteoclastic resorption with local release of bone-derived growth factors, resulting in a bone marrow micro environment less favourable for tumour-cell gowth; inhibition of neoangiogenesis; induction of tumour-cell apoptosis; synergy with cytotoxic chemotherapy; and immunomodulatory eff ects. In preclinical models, zoledronic acid synergises with chemotherapy, with the greatest effect noted when zoledronic acid was administered sequentially after chemotherapy rather than concomitantly. Guise TA. Cancer Treatment Reviews 2008; 34 (suppl 1): 19.

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7 Klinische Daten Biphosphonate und Tumorzellen im KM Phase 2 randomised trial between 3/2003, and 5/ Patients had clinical stage II III ( T2 and/or N1) newly diagnosed breast cancer, 120 women were randomly assigned to receive 4 mg zoledronic acid i.v. every 3 weeks (n=60), or no zoledronic acid (n=60), for 1 year concomitant with four cycles of neoadjuvant epirubicin (75 mg/m2) plus docetaxel (75 mg/m2) and two cycles of adjuvant epirubicin plus docetaxel. The primary endpoint was the number of patients with detectable disseminated tumor cells at 3 months. This study is registered with ClinicalTrials.gov, number NCT Aft R. Lancet Oncol 2010; 11:

8 Biphosphonate und Tumorzellen im KM At baseline, DTCs were detected in 26 of 60 patients in the zoledronic acid group and 28 of 58 patients in the control group. At 3 months, 17 of 56 patients receiving zoledronic acid versus 25 of 53 patients who did not receive zoledronic acid had detectable DTCs (p=0 054). Zoledronic acid administered with chemotherapy resulted in a decreased proportion of patients with DTCs detected in the bone marrow at the time of surgery. This study supports the hypothesis that the antimetastatic effects of zoledronic acid may be through eff ects on DTCs. Aft R. Lancet Oncol 2010; 11:

9 Resultate DTC + at baseline and 3 months DTC at baseline and At 3 months Aft R. Lancet Oncol 2010; 11:

10 Subgruppen

11 Klinische Daten: Neoadjuvante Studien Verschiedene Studien in der neo-adjuvanten Situation Einige Resultate zeigen, dass Bisphosphonate (clodronate and zoledronat) in der neoadjuvanten Situation die Zahl der kompletten Remissionen erhöhen ( antitumorale Aktivität) Fehm et al. BMC Cancer 2012, 12:308

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13 Neo-AZURE Retrospektiv wurden Daten von 205 pra- und postmenopausalen Brustkrebs-Patientinnen ausgewertet, die praoperativ Zoledronat kombiniert mit einer Chemotherapie erhalten hatten. Durch die zusatzliche Bisphosphonat-Gabe konnte die Grosse des Primartumors signifikant um 11,9 mm (43 %; p = 0,006) verringert werden. Fast doppelt so viele Frauen wiesen eine Komplettremission auf: In der alleinigen Chemotherapie-Gruppe betrug die gesamte pathologische Ansprechrate 6,9 %, wahrend sie in der Kombinationsgruppe mit Zoledronat 11,7 % betrug. Winter MC: Cancer Res 2009; 69: abstr 5101.

14 Mit Letrozole

15 Klinische Daten Early Adjuvant Studies Diel et al [1] (N = 302): oral clodronate in pts with DTC in marrow Significant benefit in DFS and OS Saarto et al [2] (N = 299): oral clodronate in stage I-III patients No benefit in DFS and OS; early harm Kristensen et al [3] (N = 953): oral pamidronate in stage I-III patients No benefit in DFS or OS Powles et al [4] (N = 1069): oral clodronate in stage I-III patients Significant benefit in DFS and OS 1. Diel IJ, et al. N Engl J Med. 1998;339: Saarto T, et al. Acta Oncol. 2004;43: Kristensen B, et al. Acta Oncol. 2008;47: Powles T, et al. J Clin Oncol. 2002;20:

16 Oral Clodronate for Adjuvant Treatment of STAGE I-III Breast Cancer (N = 1069) EFS (%) 2 yrs 5 yrs Bone Metastasis Free Survival (ITT) Placebo Clodronate At 5 yrs, HR: (95% CI: ; P =.043) Yrs Premenopausal P =.334 Postmenopausal P =.056 Premenopausal P =.448 Postmenopausal P =.017 OS (%) HR (95% CI) clodronate/placebo Benefit to clodronate Benefit to placebo OS (ITT) Clodronate (n = 98/530) Placebo (n = 129/539) HR: (95% CI: ; P =.048) Yrs Premenopausal P =.887 Postmenopausal P = HR (95% CI) clodronate/placebo at 10.5 yrs Benefit to clodronate Powles T, et al. Breast Cancer Res. 2006;8:R13. Powles T, et al. ASCO Abstract 528. Benefit to placebo

17 Welche neuere Daten für den adjuvanten Einsatz?

18 NSABP B-34: Phase III Study of Adjuvant Clodronate in Breast Cancer Primary endpoint: DFS Secondary endpoints: OS, recurrence-free interval, incidence of metastases, SREs, adverse events, and prognostic serum markers Women with operable stage I-II breast cancer receiving adjuvant standard therapy (N = 3323) R Clodronate 1600 mg QD Placebo Treatment duration: 3 yrs Median follow-up: 90.7 mos Two thirds of pts aged 50 yrs or older; one fourth were N positive Paterson A, et al. Lancet Oncol. 2012;13:

19 NSABP B-34: DFS in Women Treated With Clodronate After Tumor Removal DFS (%) Placebo Clodronate 20 HR: 0.91 (95% CI: ; P =.27) Pts at Risk, n Yrs Placebo Clodronate Paterson A, et al. Lancet Oncol. 2012;13:

20 NSABP B-34 Subset Analysis: RFI by Stratification Variable ER-positive patients ER-negative patients 4+ positive nodes 1-3 positive nodes Negative nodes Pts 50 yrs + at entry Pts < 50 yrs at entry All pts with follow-up HR = 0.8 Clodronate better Placebo better HR Paterson A, et al. SABCS Abstract S2-3.

21 NSABP B-34 Subset Analysis: DMFI, RFI, BMFI, and NBMFI in Patients 50 Yrs Endpoint for Patients 50 Yrs of Age or Older HR P Value DMFI RFI BMFI NBMFI DMFI: distant metastasis-free interval RFI: relapse-free interval BMFI: bone-metastasis-free interval NBMFI: non-bone metastasis-free interval Paterson A, et al. SABCS Abstract S2-3.

22 GAIN Trial: Phase III Study in Women With Node-Positive Breast Cancer Arm A1 Arm B1 Epirubicin 150 mg/m 2 q2w Paclitaxel 225 mg/m 2 q2w Cyclophosphamide 2000 mg/m 2 q2w Ibandronate 50 mg PO QD 2 yrs Arm A2 Epirubicin mg/m 2 Cyclophosphamide 600 mg/m 2 q2w Ciprofloxacin Pegfilgrastim Darbepoetin alfa or Epoetin beta Paclitaxel 67.5 mg/m 2 qw Capecitabine 2000 mg/m 2 Days 1-14 q3w Arm B2 Observation Ciprofloxacin Pegfilgrastim Darbepoetin alfa or Epoetin beta Möbus V, et al. SABCS Abstract S2-4.

23 GAIN: DFS and OS of Ibandronate vs Observation (ITT Population) Survival Probability (%) Product-Limit Survival Estimates With Number of Pts at Risk + Censored yr DFS, % Ibandronate: 87.6 Observation: 87.2 Cox Regression HR: (95% CI: ; P =.59) Survival Probability (%) Product-Limit Survival Estimates With Number of Pts at Risk + Censored 3-yr OS, % Ibandronate: 94.7 Observation: 94.1 Cox Regression HR: 1.04 (95% CI: ; P =.80) DFS (mos) Ibandronate Möbus V, et al. SABCS Abstract S OS (mos) Observation

24 GAIN: Subgroup Analyses of Ibandronate vs Observation DFS for Ibandronate in Subgroups pn1 pn2 pn3 ER and/or PgR positive ER and PgR negative Pre- and perimenopausal Postmenopausal Younger than 60 yrs 60 yrs or older HR: 1.04 (95% CI: ; P =.877) HR: (95% CI: ; P =.490) HR: (95% CI: ; P =.734) HR: (95% CI: ; P =.706) HR: (95% CI: ; P =.383) HR: 1.02 (95% CI: ; P =.912) HR: (95% CI: ; P =.462) HR: 1.02 (95% CI: ; P =.842) HR: (95% CI: ; P =.172) HR Better With Ibandronate Möbus V, et al. SABCS Abstract S2-4. Worse With Ibandronate

25 ABCSG-12: Study Design Key endpoints Primary: DFS at 5 yrs Secondary: relapse-free survival, OS, BMD, safety 1803 premenopausal pts with breast cancer, stage I/II (goserelin 3.6 mg/28 days) Stratified by: ER+ and/or PgR+ Age Stage Grade Lymph nodes Gnant M, et al. N Engl J Med. 2009;360: R TAM 20 mg/day ANA 1 mg/day TAM + ZA 4 mg q6m ANA + ZA 4 mg q6m Treatment 3 yrs (median follow-up: 48 mos) 3-yr BMD Long-term monitoring for 5 yrs for recurrence and survival (DFS, OS) 5-yr BMD

26 ABCSG-12 (84 Mos): DFS in Women Who Received Adjuvant ET ± ZA 100 DFS 100 OS DFS (%) Patients at Risk, n No ZA ZA Mos Since Randomization No ZA ZA P Value Events, n 132/903 98/900 Univariate HR (95% CI) 0.72 ( ).014 Multiple Cox regression HR (95% CI) 0.71 ( ) Gnant M, et al. SABCS Abstract S OS (%) Patients at Risk, n No ZA ZA Mos Since Randomization No ZA ZA P Value Events, n 49/903 33/900 Univariate HR (95% CI) 0.63 ( ).049 Multiple Cox regression HR (95% CI) 0.61( )

27 ABCSG-12 (84 Mos): First DFS Events With Adjuvant ET ± ZA First Event/Pt (n) Death without previous recurrence Secondary malignancy Contralateral breast cancer Distant recurrence Locoregional recurrence No ZA (n = 903) 19 ZA (n = 900) Gnant M, et al. SABCS Abstract S1-2.

28 ABCSG-12 (84 Mos): Age Effect on DFS Yrs of Age or Younger 100 Older Than 40 Yrs of Age DFS (%) Events, n Univariate HR (95% CI) P Value Events, n Univariate HR (95% CI) P Value Patients at Risk, n No ZA ZA No ZA 42/213 ZA 35/200 Mos Since Randomization vs no ZA (Log-rank) 0.87 ( ) Patients at Risk, n No ZA ZA No ZA 90/690 ZA 63/700 Mos Since Randomization vs no ZA (Log-rank) 0.66 ( ) Gnant M, et al. SABCS Abstract S1-2.

29 ABCSG 12 Gnant M. Lancet Oncol 2011; 12:

30 ABCSG-12: Change in BMD at Yrs 3 and 5 No ZA ZA 10 Tamoxifen Anastrozole Tamoxifen Anastrozole Percent Change in LS BMD (g/cm 2 ) From Baseline P < NS Months P = NS +5.2 P = NS +3.1 NS Months P <.0001 Gnant M, et al. Lancet Oncol. 2008;9:

31 AZURE: Phase III Study of Adjuvant ZA in High-Risk, Localized Breast Cancer Accrual September 2003 to February 2006 Women with stage II/III breast cancer (N = 3360) Country, n Centers Patients United Kingdom Ireland Australia Spain Portugal 1 32 Thailand 2 25 Taiwan 2 13 Coleman RE, et al. N Engl J Med. 2011;365: R 6 doses q3-4w Standard therapy Standard therapy + ZA 4 mg 8 doses q3m Mos ZA treatment duration: 5 yrs 5 doses q6m Primary endpoint: DFS, with recurrence defined as date first suspected

32 AZURE: DFS and Invasive DFS 100 DFS DFS 100 IDFS IDFS Surviving (%) ZA (n = 1681) Control (n = 1678) Adjusted HR: 0.98 (95% CI: ; P =.79) Surviving (%) ZA (n = 1681) Control (n = 1678) Adjusted HR: 0.98 (95% CI: ; P =.73) Yrs Yrs Patients at Risk, n ZA Control Coleman RE, et al. N Engl J Med. 2011;365: Patients at Risk, n ZA Control

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34 AZURE: Invasive DFS and OS by Menopausal Status Proportion Alive and Invasive Disease Free (%) IDFS: Pre-, Peri-, and Unknown Menopausal Status Adjusted HR: 1.15 (95% CI: ; P =.11) 288 vs 256 events Pts at Risk, n ZA No ZA Mos From Randomization Proportion Alive and Invasive Disease Free (%) IDFS: > 5 Yrs Postmenopausal Adjusted HR: 0.75 (95% CI: ; P =.02) 116 vs 147 events Pts at Risk, n ZA No ZA Mos From Randomization OS: Pre-, Peri-, and Unknown Menopausal Status OS: > 5 Yrs Postmenopausal Proportion Alive (%) Adjusted HR: 0.97 (95% CI: ; P =.81) 161 vs 165 events Pts at Risk, n ZA No ZA Mos From Randomization Coleman RE, et al. N Engl J Med. 2011;365: Proportion Alive (%) Adjusted HR: 0.74 (95% CI: ; P =.04) 82 vs 111 events Pts at Risk, n ZA No ZA Mos From Randomization

35 AZURE: Treatment Effect on Invasive DFS by Menopausal Status Menopausal Group Description High estrogen environment Pre- + < 5 yrs postmenopausal + unknown status > 5 yrs postmenopausal Low estrogen environment Total: -1% ± 7% Z =.13; P =.9 HR: 0.75 (95% CI: ) Typical Odds Ratio Odds Reduction (± SD) HR: 1.15 (95% CI: ) n = events n = events χ 2 1 (heterogeneity) = 7.91; P =.005 Coleman RE, et al. N Engl J Med. 2011;365:

36 AZURE: Treatment Effects on First Bone Recurrence by Menopausal Status Menopausal Group Description Pre + < 5 yrs post + unknown status Typical Odds Ratio HR: 0.86 (95% CI: ) > 5 yrs postmenopausal HR: 0.88 (95% CI: ) χ 2 1 (heterogeneity) = 0.14; P =.70 Adjusted for imbalances in ER, lymph node status, and T stage. Coleman RE, et al. N Engl J Med. 2011;365:

37 Treatment Effects on First IDFS Recurrence Outside Bone by Menopausal Status Menopausal Group Odds Ratio Pre-, peri-, and unknown menopause HR: 1.32 (95% CI: ) > 5 yrs postmenopausal HR: 0.70 (95% CI: ) Total: 6% ± 8 Z =.79, P = χ 2 1 (heterogeneity) = 14.00; P = <.001 Adjusted for imbalances in ER, lymph node status, and T stage. Coleman RE, et al. N Engl J Med. 2011;365:

38 ONJ 26 confirmed cases of ONJ (2.1%; 95% CI: ) 3 during ZA treatment for metastatic bone disease Median number of ZA infusions: 13 (range: 1-19) Median time from start of treatment: 863 d (range: ) Yrs Pts at Risk, n Coleman RE, et al. N Engl J Med. 2011;365: Rathbone E, et al. J Clin Oncol. Under revision.

39 ZO-FAST: Trial Design Key endpoints: Primary: BMD at 12 mos Secondary: BMD at 36 and 60 mos, disease recurrence, fractures, safety Breast cancer Stage I to IIIa (N = 1065) Postmenopausal or amenorrheic due to cancer treatment ER + and/or PgR + T-score -2.0 R Letrozole + immediate ZA (4 mg every 6 mos) Letrozole + Delayed ZA If 1 of the following occurs: BMD T-score < -2 Clinical fracture Asymptomatic fracture at 36 mos Treatment duration: 5 yrs Coleman R, et al. Ann Oncol In press. ClinicalTrials.gov. NCT

40 ZO-FAST: Final 5-Yr DFS With Adjuvant Letrozole and ZA DFS (%) ITT Population HR: 0.66; log-rank P =.0375 IM-ZA 4 mg (42 events) D-ZA 4 mg (62 events) Pts at Risk, n Mos on Study IM-ZA D-ZA Censored Analysis* Pts at Risk, n Mos on Study IM-ZA D-ZA *Censored pts at initiation of D-ZA (n = 144). Coleman R, et al. Ann Oncol. 2012;[Epub ahead of print]. DFS (%) HR: 0.62; log-rank P =.024 IM-ZA 4 mg (42 events) D-ZA 4 mg (53 events)

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42 Variable Efficacy in an Unselected Population Study Overall DFS Result (95% CI) P Value AZURE (n = 3359) [1] 0.98 ( ).79 ABCSG XII (n = 1803) [2] 0.71 ( ).011 ZO-FAST (n = 1065) [3] 0.66 ( ).04 NSABP-B34 (n = 3323) [4] 0.91 ( ).27 CLODROPLAC (n = 1069)* [5] 0.69 ( ).043 GAIN (n = 2994) [6] 0.95 ( ).59 *Analysis relates to bone metastasis-free survival. 1. Coleman RE, et al. N Engl J Med. 2011;365: Gnant M, et al. SABCS Abstract S De Boer R, et al. SABCS Abstract S Paterson A, et al. SABCS Abstract S Powles T, et al. Breast Cancer Res. 2006;8:R Mobus V, et al. SABCS Abstract S2-4.

43 Consistent Efficacy in Postmenopausal Women Study Postmenopausal DFS (95% CI) P Value AZURE (n = 1041) [1] 0.75 ( ).02 ABCSG XII (n = 1390) [2] 0.66 ( )*.013 ZO-FAST (n = 1065) [3] 0.66 ( ).04 NSABP-B34 (n = 2139) [4] 0.68 ( ).013 CLODROPLAC (n = 539) [5] 0.66 ( ).007 GAIN (n = 1557) [6] 0.75 ( ).17 *Includes patients > 40 yrs on goserelin; no significant effect for patients < 40 yrs. Analysis relates to OS. 60 yrs at study entry. 1. Coleman RE, et al. N Engl J Med. 2011;365: Gnant M, et al. SABCS Abstract S De Boer R, et al. SABCS Abstract S Paterson A, et al. SABCS Abstract S Powles T, et al. Breast Cancer Res. 2006;8:R Mobus V, et al. SABCS Abstract S2-4.

44 Nebenwirkungen der Bisphosphonate

45 Rizzoli R.Medizin Forum. 2012;12(16):323 6 NW der Bisphosphonate Kurzfristige Myalgien, Arthralgien, Fieber, grippeähnliche Symptome, Kopfschmerzen Knochenschmerzen Dysphagie, Ösophagitis und ösophageale oder gastrische Ulzera Kardiale NW, VHF Niereninsuffizienz

46 NW der Bisphosphonate Langfristige Osteonekrose des Kiefers Atypische subtrochantere Frakturen Oesophagiskarzinome (?)

47 Rolle des Oestrogenmangel Ein Vergleich der verschiedenen Studienpopulationen (ABCSG-12, ZOFAST, AZURE, Subgruppenanalyse AZURE) zeigt, dass es hinsichtlich Ostrogenmilieu, Rezidivrisiko und Primartherapie bedeutende Unterschiede bestehen. Die entscheidende Rolle hinsichtlich der Antitumorwirkung von Bisphosphonaten scheint die Ostrogensituation zu sein.

48 Rolle der Oestrogene Der Vergleich lasst den Schluss zu, dass bei einer adjuvanten Bisphosphonat-Therapie bei Frauen mit absolutem Ostrogenmangel (wie in der ABSCG-12) bzw. in einem Ostrogenmangelmilieu (wie in ZOFAST und AZURE) eine Antitumor- Wirkung besteht.

49 Warum? Erklaren lasst sich die gute Wirksamkeit von Bisphosphonaten bei Frauen mit niedrigem Ostrogenspiegel durch die Tatsache, dass es durch den Hormonmangel zu einem deutlich gesteigerten Knochenstoffwechsel kommt mit einem massiven Anstieg der Osteoklastenanzahl, - funktion und -aktivitat und infolgedessen u. a. zu einer erhohten Freisetzung von Zytokinen wie z. B. IL 1, IL 6, TGF-s, PTHrP, RANKL etc., die wiederum schlafende Tumorzellen stimulieren bzw. aktivieren konnen. In dieser Situation supprimiert die zeitgleich durchgefuhrte Bisphosphonat-Therapie die Osteoklastenfunktion und damit deren potentielle negative Auswirkungen auf bestehende Tu- morzellen.

50 Sind alle Bisphosphonate gleich?

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52 Ich weiss es nicht! Clodronat Ibandronat Zoledronat

53 ZA Studies: DFS Comparison ZO-FAST [1] 104 events AZURE - > 5 yrs postmenopausal [2] 263 events ABCSG-12 [3] 230 events 0.66 N = n = N = 1803 P Value HR 1. De Boer R, et al. SABCS Abstract S Coleman RE, et al. N Engl J Med. 2011;365: Gnant M, et al. SABCS Abstract S1-2.

54 Schlussfolgerungen (wenn möglich...)

55 St. Gallen 2013 The Panel considered several situations in which bisphosphonates might be used with the aim of improving disease-free survival, but did not endorse such treatment for this purpose in any group, though a substantial minority felt that premenopausal patients receiving an LHRH agonist plus tamoxifen or clearly postmenopausal patients might derive benefit from such treatment. Denosumab was not endorsed for adjuvant use.

56 Conclusions Targeting the host environment may complement activity of direct anticancer treatments Adjuvant benefit from bone-targeted treatment appears to be dependent on a low reproductive hormone environment Biologic mechanisms need further evaluation Adjuvant ZA could be considered in women with a low estrogen environment Prevent bone loss and fragility fracture Potentially improve disease outcomes

57 Offene Punkte Postmenopausal (natürlich oder chemisch temporär ) Welcher Bisphosphonat? Dosis?/Intervalle? Dauer? Langzeit Toxizität? (z. B. bei späteren SS?)

58 Ongoing Phase III Trials of Antitumor Properties of Bone-Targeted Agents Trial Regimen Primary Outcomes SWOG 0307 NATAN D-CARE HOBOE SUCCESS ZA vs clodronate vs ibandronate ZA after neoadjuvant chemotherapy Denosumab 120 mg/mo for 6 mos, then 120 mg q3m vs placebo Triptorelin + TAM vs triptorelin + letrozole vs triptorelin + letrozole + ZA FEC-D vs FEC-DG 2 yrs of ZA vs 5 yrs of ZA DFS, OS EFS Bone metastasis free survival DFS DFS ABCSG-18 Denosumab 60 mg q6m vs placebo Time to first fracture

59 Würden Sie Bisphosphonate in der adjuvanten Situation brauchen? Oder brauchen Sie sie bereits? A. Bei allen Patientinnen, unabhängig vom Frakturrisiko B. Bei allen postmenopausalen Patientinnen,, unabhängig vom Frakturrisiko C. Nur bei Patientinnen mit Osteopenie/ Osteoporose? D. Unsicher

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