Efficacy and safety of abiraterone acetate plus prednisone in Japanese patients with newly diagnosed, metastatic hormone-naïve prostate cancer: a subgroup analysis of LATITUDE, a randomized, double-blind, placebo-controlled, Phase 3 study.

OBJECTIVES: To evaluate the efficacy and safety of abiraterone acetate plus prednisone (AAP) plus androgen-deprivation therapy (ADT) in Japanese subgroup with newly diagnosed, metastatic hormone-naïve prostate cancer (mHNPC) from Phase 3, randomized, global LATITUDE study. METHODS: Men with mHNPC having ≥2 of 3 high-risk factors (Gleason score ≥8, ≥3 bone lesions or measurable visceral metastases) randomly received abiraterone acetate 1000-mg+ prednisone 5-mg+ADT (AAP group) or ADT+Placebos (Placebo group). Coprimary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS). RESULTS: Of total 1199 patients in the LATITUDE study, 70 (5.8%) were Japanese (n = 35 each in the AAP and placebo group). After a median follow-up of 35.02 months (range: 2.5-42.3), median OS was not reached in both AAP group and placebo group (HR: 0.635; 95% CI, 0.152-2.659) and the median length of rPFS was not reached in the AAP group and was 22 months in the placebo group (HR:0.219; 95% CI, 0.086-0.560). The most frequently reported adverse events (>20% in either group) in the Japanese subgroup were hypertension, nasopharyngitis, weight increased, hypokalemia, hot flush, back pain, hyperglycemia, ALT and AST elevation. The incidence of Grade 3 or 4 adverse events was 65.7% (23/35) in the AAP group and 20% (7/35) in the placebo group. The efficacy and safety findings of Japanese subgroup were consistent with that of the overall study population. CONCLUSION: Treatment with AAP plus ADT has shown a positive risk-benefit balance and may serve as a new treatment option to improve the prognosis of Japanese mHNPC patients with high-risk features.

In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17ß-hydroxysteroid dehydrogenase type 5 (17ßHSD5; AKR1C3).

BACKGROUND: Aldo-keto reductase 1C3 [AKR1C3;17ß-hydroxysteroid dehydrogenase type 5 (17ßHSD5)], plays a crucial role in persistent production of androgens despite castration, by catalysing conversion of the adrenal androgens dehydroepiandrosterone and androstenedione (AD) into androstenediol and testosterone (T). Hence, AKR1C3 is a promising therapeutic target in castration-resistant prostate cancer, as combination of an AKR1C3 inhibitor and a gonadotropin-releasing hormone analogue may lead to complete androgen blockade. This study describes the preclinical characterisation of the novel AKR1C3 inhibitor ASP9521. METHODS: The inhibitory effect of ASP9521 on AKR1C3-mediated conversion from AD into T was evaluated both in vitro and in vivo, using CWR22R xenografted mice. The effect of ASP9521 on PSA production and cell proliferation was tested using LNCaP cells stably expressing human AKR1C3 (LNCaP-AKR1C3). Pharmacokinetics of ASP9521 were studied in rats, dogs and cynomolgus monkeys. RESULTS: ASP9521 inhibited conversion of AD into T by recombinant human or cynomolgus monkey AKR1C3 in a concentration-dependent manner (IC50,human: 11 nmol/L; IC50,monkey: 49 nmol/L). ASP9521 showed >100-fold selectivity for AKR1C3 over the isoform AKR1C2. In LNCaP-AKR1C3 cells, ASP9521 suppressed AD-dependent PSA production and cell proliferation. In CWR22R xenografts, single oral administration of ASP9521 (3 mg/kg) inhibited AD-induced intratumoural T production and this inhibitory effect was maintained for 24 h. After oral administration, ASP9521 was rapidly eliminated from plasma, while its intratumoural concentration remained high. The bioavailability of ASP9521 after oral administration (1 mg/kg) was 35 %, 78 % and 58 % in rats, dogs and monkeys, respectively. CONCLUSIONS: ASP9521 is a potent, selective, orally bioavailable AKR1C3 inhibitor.

Discovery of 2-methyl-1-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propan-2-ol: a novel, potent and selective type 5 17ß-hydroxysteroid dehydrogenase inhibitor.

Type 5 17ß-hydroxysteroid dehydrogenase (17ß-HSD5), also known as aldo-keto reductase 1C3 (AKR1C3), is a member of the aldo-keto reductase superfamily of enzymes and is expressed in the human prostate. One of the main functions of 17ß-HSD5 is to catalyze the conversion of the weak androgen, androstenedione, to the potent androgen, testosterone. The concentration of intraprostatic 5α-dihydrotestosterone (DHT) in patients following chemical or surgical castration has been reported to remain as high as 39% of that of healthy men, with 17ß-HSD5 shown to be involved in this androgen synthesis. Inhibition of 17ß-HSD5 therefore represents a promising target for the treatment of castration-resistant prostate cancer (CRPC). To investigate this, we conducted high-throughput screening (HTS) and identified compound 2, which displayed a structure distinct from known 17ß-HSD5 inhibitors. To optimize the inhibitory activity of compound 2, we first introduced a primary alcohol group. We then converted the primary alcohol group to a tertiary alcohol, which further enhanced the inhibitory activity, improved metabolic stability, and led to the identification of compound 17. Oral administration of compound 17 to castrated nude mice bearing the CWR22R xenograft resulted in the suppression of androstenedione (AD)-induced intratumoral testosterone production. Compound 17 also demonstrated good isoform selectivity, minimal inhibitory activity against either CYP or hERG, and enhanced pharmacokinetic and physicochemical properties.

Burden of illness of chemotherapy in castration-resistant prostate cancer patients in Japan: a retrospective database analysis.

OBJECTIVE: The objective was to assess the burden of chemotherapy for castration-resistant prostate cancer (CRPC) in Japan. METHODS: Utilizing a large administrative hospital database we compared a set of outcome measures 12 months before and after initiation of chemotherapy, namely total medical costs, number of outpatient visits, number of hospital admissions and number of days spent in hospital. RESULTS: A total of 598 CRPC patients were identified in the database. Total healthcare costs increased from 143,578 Japanese Yen (JPY) per patient per month (PPPM), before chemotherapy, to 333,628 JPY after start of chemotherapy. The number of hospital admissions increased by 280%, and the number of days spent in hospital by 380%. CONCLUSIONS: The overall costs of chemotherapy for patients diagnosed with castration-resistant prostate cancer in Japan are high. Our findings can serve as a basis for health economic evaluations.

Possible oncogenic potential of DeltaNp73: a newly identified isoform of human p73.

p73, a recently identified gene highly homologous to p53, can transactivate p53 target genes and induce apoptosis. Here we report the identification of an NH(2)-terminal truncated isoform of human p73, DeltaNp73, which is capable of suppressing p53- and p73-dependent transactivation. We speculate that this suppression is achieved by competing for the DNA binding site in the case of p53 and by direct association in the case of TAp73. Expression of DeltaNp73 in cancer cell lines also inhibited suppressive activity of p53 and TAp73 in colony formation, implying possible involvement of DeltaNp73 in oncogenesis by inhibiting the tumor-suppressive function of p53 and TAp73. Also reported is the identification of TAp73eta, a new member of the COOH-terminal truncated isoform of p73 and tissue-specific expression of these isoforms, along with other previously identified p73 isoforms.