Zusammenfassung
Einleitung: Die Ergebnisse der HALT-Prostatakarzinom-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 Mona-ten
unter Behandlung mit Denosumab vs. Placebo ermittelt.
Ergebnisse: Zu Studienbeginn wiesen 1174 bzw. 80 % der Studienteilnehmer einen BMDT-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 Mona-ten 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
HALT-Studie 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
