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Safety data from a phase II trial of Radium-223 dichloride plus Enzalutamide versus Enzalutamide alone in men with metastatic castration refractory prostate cancer


Radium-223 dichloride ( Ra-233; Xofigo ), a bone targeting alpha radiopharmaceutical, and Enzalutamide ( Xtandi ), are approved for metastatic castration refractory prostate cancer ( mCRPC ).
Per SWOG0421, the subset of men with mCRPC with the highest bone metabolism marker levels had improved survival with concomitant decrease in these markers on treatment ( Rx ) with Atrasentan, a bone targeting agent ( Lara P et al, JNCI, 2014 ).

The hypothesis was that tretament with Radium-223 + Enzalutamide will be safe and feasible, and decrease bone metabolism markers compared to Enzalutamide alone.

In a phase 2 trial, men with progressive CRPC on continuous androgen deprivation therapy were included.
Radium-223 was administered at standard dose of 55 kBq/kg IV Q4 weeks x 6, and Enzalutamide at 160 mg orally daily until disease progression or unacceptable toxicities.

Primary objectives were: 1) safety and feasibility of combining Radium-223 + Enzalutamide, 2) changes in the bone metabolism markers with treatment.
Secondary objectives included time to progression, skeletal events, percent change in opioid use.

The pre-specified primary safety endpoint was the proportion of patients treated with the combination who experienced grade 3+ cytopenias relative to historic controls ( 21% ) from the phase 3 ALSYMPCA trial using an exact binomial test with a one-sided 0.05 significance level.
All adverse events between arms were compared using Fisher’s Exact Test.

Safety data were presented. 49 patients were accrued between 2014-2017. 35 men received treatment with Radium-223 + Enzalutamide and 14 men with Enzalutamide alone.
The primary safety endpoint occurred in 3 patients in the combination arm ( incidence 8.6%, n = 35 patients ), and in 0 patients in the Enzalutamide only arm ( n=14 ).

These were similar to historic data ( ALSYMPCA trial ) of monotherapy with Radium-223 ( P = 1.00 ), and not different between arms ( P=0.55 ).

Serious adverse events, regardless of attribution were similar in both arms ( P=0.66 ).

In conclusion, combining Radium-223 + Enzalutamide is safe and feasible in men with progressive mCRPC with no difference observed in serious adverse events regardless of attribution between two arms.
Specifically, there was no incidence of skeletal related events in either arm. ( Xagena )

Source: ASCO ( American Society of Clinical Oncology ) Meeting, 2018

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