Definition , mechanisms of development and current treatments of castration-resistant prostate cancer

Prostate cancer is initially androgen dependent, and androgen deprivation therapy is the first-line treatment for advanced disease. Most patients respond to castration; however, tumors eventually become castration-resistant prostate cancer (CRPC). Nevertheless, androgen and the androgen receptor (AR) remain active, and affect the progression of CRPC. More effective androgen suppression or AR-targeted therapies can be useful to treat such patients. The mechanisms underlying the development of CRPC include AR hypersensitivity, intra-tumoral androgen synthesis, changes in AR ligand specificity due to mutations, ligand-independent AR activation, pathway(s) bypassing the AR and the proliferation of androgen-independent tumor cells. Historically, the primary endpoint of CRPC treatment has been palliation. In 2004, docetaxel became the first chemotherapeutic agent to demonstrate a significant survival benefit. In 2010, cabazitaxel was proven to prolong survival after docetaxel resistance. Also in 2010, Sipuleucel-T was approved as a cell-based cancer immunotherapy, and an adrenal androgen inhibitor, abiraterone acetate, was revealed to prolong the survival of patients with CRPC. In 2013, a second-generation anti-androgen, enzalutamide, was shown to improve the survival of CRPC patients, and radium-223, a bone-targeted agent, was approved for CRPC. Determining how to apply these new agents for each patient in clinical practice is an important issue. 和文要旨 前立腺癌はアンドロゲン依存癌である。内分泌療法を施行した場合当初は治療に奏功するが,次第に 治療抵抗性となる。この機序には,腫瘍のアンドロゲン産生,アンドロゲン受容体(AR)増幅,ARの リガンド特異性の喪失,ARを介さない経路などがある。多くでARを介した増殖経路が残っていて去勢 状態でも増殖に関与しており,去勢抵抗性前立腺癌と呼ぶ。去勢抵抗性前立腺癌に対する治療は従来緩 和目的のみであったが,2004年にタキサン系の抗がん剤であるドセタキセルで生存期間延長効果が初め て示された。その後,タキサン系の薬剤としてカバジタキセル,免疫治療としてシプルーセルT,副腎 性アンドロゲン産生抑制剤であるアビラテロン,第2世代抗アンドロゲン剤であるエンザルタミド,放 射線同位元素であるRa-223で予後改善効果が認められている。今後これらの薬剤を実際の症例にどのよ うに使用していくかが大きな課題である。