がん悪液質に対するenobosarm

選択的アンドロゲン受容体モジュレーターenobosarmのがん悪液質と身体機能に対する効果をみたフェーズ2のRCTを紹介します。

Adrian S Dobs, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. The Lancet Oncology, http://dx.doi.org/10.1016/S1470-2045(13)70055-X

リサーチクエスチョンは以下の通りです。

P：肥満がなく過去6ヶ月間に2％以上の体重減少をみとめたがん患者に
I：enobosarm（1mg、3mg）を113日間投与すると
C：プラセボと比較して
O：除脂肪体重（DEXAで測定）が増加する
D：RCT

結果ですが、プラセボ群では中央値0·02 kgの変化でしたが、1mg投与群では中央値1·5 kg, 幅−2·1 to 12·6、3mgでは中央値1·0 kg,幅 −4·8 to 11·5と前後比較で有意に除脂肪体重が増加しました。プラセボとの比較では1mg群がp=0.066、3mg群がp=0.041でした。

主な有害事象はがんの進行、肺炎、発熱性好中球減少症でしたが、プラセボ群とenobosarm（1mg、3mg）で著明な差はなく、enobosarmによるものではないと思われました。以上よりがん悪液質に対してenobosarmは除脂肪体重を増加させる可能性があるという結論です。

今回の研究では除脂肪体重が一次アウトカムでしたが、今後は身体機能・ADL・QOL・生存期間を一次アウトカムとした研究も行われるとよいですね。選択的アンドロゲン受容体モジュレーターenobosarmのフェーズ3の臨床研究も行われているようですので、その結果にも期待したいところです。

Summary

Background

Cancer-induced muscle wasting begins early in the course of a patient's malignant disease, resulting in declining physical function and other detrimental clinical consequences. This randomised, double-blind, placebo-controlled phase 2 trial assessed the efficacy and safety of enobosarm, a selective androgen receptor modulator, in patients with cancer.

Methods

We enrolled male (>45 years) and female (postmenopausal) patients with cancer who were not obese and who had at least 2% weight loss in the previous 6 months. Participants were randomly assigned (1:1:1 ratio, by computer generated list, block size three, stratified by cancer type) to receive once-daily oral enobosarm 1 mg, 3 mg, or placebo for up to 113 days at US and Argentinian oncology clinics. The sponsor, study personnel, and participants were masked to assignment. The primary endpoint was change in total lean body mass from baseline, assessed by dual-energy x-ray absorptiometry. Efficacy analyses were done only in patients who had a baseline and an on-treatment assessment in the protocol-specified window of within 10 days before baseline or first study drug, and within 10 days of day 113 or end of study (evaluable efficacy population). Adverse events and other safety measurements were assessed in the intention-to-treat (safety) population. This trial is registered with ClinicalTrials.gov, number NCT00467844.

Findings

Enrolment started on July 3, 2007, and the last patient completed the trial on Aug 1, 2008. 159 patients were analysed for safety (placebo, n=52; enobosarm 1 mg, n=53; enobosarm 3 mg, n=54). The evaluable efficacy population included 100 participants (placebo, n=34; enobosarm 1 mg, n=32; enobosarm 3 mg, n=34). Compared with baseline, significant increases in total lean body mass by day 113 or end of study were noted in both enobosarm groups (enobosarm 1 mg median 1·5 kg, range −2·1 to 12·6, p=0·0012; enodosarm 3 mg 1·0 kg, −4·8 to 11·5, p=0·046). Change in total lean body mass within the placebo group (median 0·02 kg, range −5·8 to 6·7) was not significant (p=0·88). The most common serious adverse events were malignant neoplasm progression (eight of 52 [15%] with placebo vs five of 53 [9%] with enobosarm 1 mg vs seven of 54 [13%] with enobosarm 3 mg), pneumonia (two [4%] vs two [4%] vs three [6%]), and febrile neutropenia (three [6% vs one [2%] vs none). None of these events were deemed related to study drug.

Interpretation

Cancer cachexia is an unmet medical need and our data suggest that use of enobosarm might lead to improvements in lean body mass, without the toxic effects associated with androgens and progestational agents.