Zusammenfassung
Einleitung
Die Ergebnisse der HALT-Prostata-karzinom Studie (1) zeigten, dass Denosumab bei Prostatakarzinompatienten
unter hormonablativer Therapie (HALT) die Knochenmineraldichte (BMD) gegenüber Placebo
an allen Messorten signifikant erhöhte und die Inzidenz vertebraler Frakturen nach
36 Monaten signifikant um 62 % senkte. Keine Unterschiede wurden hinsichtlich der
Zeit bis zur ersten klinischen Fraktur (jegliche nonvertebrale oder klinisch vertebrale
Fraktur) beobachtet. In einer Post-hoc-Analyse wurde nun überprüft, ob Denosumab auch
bei Patienten mit normaler bis osteopenischer Knochendichte das Risiko für neue vertebrale
Frakturen reduziert.
Methoden
Hierzu wurde bei allen Teilnehmern der HALT-Studie (n = 1468) mit einem BMD-T-Score
> –2,5 an Lendenwirbelsäule (LWS), Gesamthüfte und Schenkelhals sowie auswertbarem
Frakturstatus die Inzidenz neuer vertebraler Frakturen nach 36 Monaten unter Behandlung
mit Denosumab vs. Placebo ermittelt.
Ergebnisse
Zu Studienbeginn wiesen 1174 bzw. 80 % der Studienteilnehmer einen BMD-T Score > –2,5
an allen drei Messorten auf. 1087 bzw. 74 % der Studienteilnehmer erfüllten die Kriterien
für die Frakturauswertung. In dieser Subgruppe reduzierte Denosumab das Risiko für
vertebrale Frakturen nach 36 Monaten gegenüber Placebo signifikant um 61 % (Placebo:
2,8 %; Denosumab: 1,1 %; p = 0,0386). Weitere Frakturendpunkte wurden nicht untersucht.
Fazit
Denosumab reduzierte das Risiko für vertebrale Frakturen bei Patienten der HALTStudie
mit normaler und osteopenischer Knochendichte in ähnlichem Ausmaß wie im Gesamtkollektiv.
Summary
Introduction
Results from the HALT Prostate Cancer Trial (1) showed that denosumab increased bone
mineral density (BMD) compared with placebo in men receiving androgen deprivation
therapy (ADT; bilateral orchiectomy or GnRH-agonist therapy planned for ≥ 12 months)
for nonmetastatic prostate cancer at all sites measured (lumbar spine [LS], total
hip, femoral neck, 1/3 distal radius, and whole body). Of note, denosumab also decreased
the cumulative incidence of new vertebral fractures by 62 % at 36 months (3.9 % in
the placebo group and 1.5 % in the denosumab group, relative risk, 0.38; 95 % confidence
interval [CI], 0.19 to 0.78; p = 0.006). We conducted a post-hoc subgroup analysis
to determine if non-osteo-porotic patients also benefit from a reduction in fracture
risk. Patients from the HALT Prostate Cancer Trial (n = 1,468) were included in this
subgroup analysis, if their respective lowest baseline BMD T-Score at LS, total hip,
or femoral neck was > –2.5. Incidence of new vertebral fractures between the denosumab
and the placebo groups was compared after 36 months for all participants of the Vertebral
Fracture Analysis Subset (VFAS: participants with baseline fracture status and more
than one post baseline fracture evaluation) of this subgroup.
Results
A total of 1,174 patients (80 % of all enrolled patients) had a baseline BMD T-Score
> –2.5 at all three sites and 1,087 (74 % of all enrolled patients) were included
in the VFAS. Patients who received denosumab had a significantly decreased incidence
of new vertebral fractures at 36 months (1.1 %, vs. 2.8 % with placebo; relative risk
0.39; 95 % CI 0.15 to 0.99; p = 0.0386), which was similar to the reduction in the
total HALT Prostate Cancer Trial population (relative risk, 0.38, see above). In an
additional analysis excluding patients with prevalent vertebral fractures at baseline
(n = 845; VFAS n = 789), fracture incidence with denosumab (3/413 or 0.7 %) was still
significant lower than with placebo (10/376 or 2.7 %) in the subgroup of non-osteo-porotic
men (relative risk 0.27; 95 % CI 0.08 to 0.99; p = 0.0335). When analysing fracture
risk subgroups according to the major DVO (Dachverband Osteologie) criteria (age,
gender, T-score, and ADT) at baseline, the risk for new vertebral fractures in the
low risk subgroup (10-year fracture risk for vertebral and hip fractures ≤ 30 %) was
significantly reduced with denosumab compared with placebo (denosumab: 6/577 [1.0
%]; placebo: 16/560 [2.9 %]; relative risk 0.36; 95 % CI 0.14 to 0.92; p = 0.0248).
There were no significant differences in the reduction of new vertebral fractures
between subgroups based on minimal BMD T-Score (normal, osteopenic, or osteo-porotic),
indicating BMD-independent efficacy of denosumab.
Conclusion
In summary, denosumab increased BMD at all sites in men receiving ADT for nonmetastatic
prostate cancer. In addition, a reduction in the incidence of new vertebral fractures
was shown with denosumab vs. placebo. Fracture risk reduction was similar in patients
with BMD in the normal to osteopenic range as seen in the entire population, even
after exclusion of men with prevalent vertebral fractures. A significant reduction
in fracture risk was also observed in patients at low fracture risk according to DVO
guidelines.
Schlüsselwörter Denosumab - ADT - Prostatakarzinom - Osteoporose - Frakturrisiko
Keywords Denosumab - ADT - prostate cancer - osteoporosis - fracture risk
