RA, a bone targeting alpha radiopharmaceutical, and EZ, are approved for mCRPC. Per phase 3 SWOG0421 trial, subset of men with mCRPC with the high serum bone metabolism markers (BMM) had improved survival with concomitant decrease in these markers on treatment (Rx) with atrasentan, a bone targeting agent (Lara P et al, JNCI, 2014). Our hypothesize was that Rx with RA+ EZ will be safe, and decrease bone metabolism markers compared to EZ alone.
In this phase 2 trial (NCT02199197), men with progressive mCRPC were treated with EZ (160 mg daily) ± RA (standard dose of 55 kBq/kg IV Q4 weeks x 6), until disease progression or unacceptable toxicities. Primary objectives: 1) changes in N-telopeptide compared from baseline to end of treatment or disease progression (whichever occurred first) between the two arms, and 2) safety of combining RA+EZ. Secondary objectives: changes in 4 other markers of bone resorption or formation, and clinical outcomes. The bone markers were compared between treatment arms on the log scale using Analysis of Covariance (ANCOVA) with baseline bone marker values as a covariate.
Combining RA+EZ was safe (2018 ASCO annual meeting abstract: 5057). Efficacy data are presented here. After a safety lead in phase (n = 8), 39 men were randomized (2:1) to RA+EZ vs EZ. The study met the primary endpoint with a significant decline in the N-telopeptide levels in RA+EZ vs EZ. There was a significant decline in all but one BMMs in RA+ EZ vs EZ alone. (Table). The clinical outcomes favored RA+EZ (data will be presented in the meeting).Table: 825P
|Marker||Ratio of RA+EZ to EZ||95% CI||P-value|
|Bone Specific Alk Phos||0.38||0.27,0.54||<0.001|
|Procollagen 1 Intact N-Terminus||0.52||0.35,0.78||<0.001|
Per SWOG0421 trial, high BMMs in men with mCRPC portends poor prognosis and have improved outcomes with bone targeting agent atrasentan with concomitant decline in BMMs. In the current study, BMMs significantly declined with RA+EZ vs EZ, thus providing the rationale for combining RA with EZ.
Clinical trial identification
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All authors have declared no conflicts of interest.