Discussion
fingertip numbness, tetany, PD, hormone-sensitive prostate cancer, prostate cancer
LIVER, PROSTATE CANCER, HORMONE-SENSITIVE PROSTATE CANCER
The GnRH antagonist SHR7280 demonstrated acceptable tolerability. PK results revealed a rapid onset of action and dose-dependent plasma exposure of SHR7280 within the dose range of 100 to 1000 mg BID, with minimal accumulation. PD results showed that SHR7280 inhibited LH, FSH, and testosterone concentrations in a dose-dependent manner. Medical castration was achieved at doses of 800 and 1000 mg from day 2 and maintained for 48 h after the last dose.The safety results indicated good tolerability of SHR7280 in healthy men receiving SHR7280 tablets twice daily for 14 consecutive days within the dose range of 100 to 1000 mg. The incidence of AEs did not increase with increasing drug dose. The overall incidence of AE and treatment-related AE, as well as the severity of AE in SHR7280 group, were similar to those in the placebo group (incidence of AE, 76.8% vs 85.7%; incidence of TRAE, 75.0% vs 85.7%; incidence of moderate AEs, 1.8% vs 7.1%). Liver function-related AEs, such as increased blood bilirubin, increased alanine aminotransferase, and increased aspartate aminotransferase, occurred at similar incidence in the SHR7280 and placebo groups, were all mild in severity, and all resolved without special intervention. However, close monitoring of liver function indicators in participants receiving long-term use of SHR7280 is necessary in further studies due to the possibility that SHR7280 may have an impact on liver function. Additionally, the incidence of decreased blood calcium was higher in the SHR7280 group than in the placebo group. Although the severity was judged as mild, and the subjects did not experience fingertip numbness, tetany, or other symptoms, attention should be paid to decreased blood calcium in future studies of SHR7280. Common AEs, including hot flush and QTc interval prolongation observed with relugolix, were not reported in subjects treated with SHR7280 [The PK profiles of SHR7280 were comparable to those of other oral GnRH antagonists, such as elagolix and relugolix [The PD results of SHR7280 were also consistent with those reported for GnRH antagonists. SHR7280 demonstrated quick and sustainable suppression of LH, FSH, and testosterone levels, indicating its potential as a novel GnRH antagonist option. The prompt and rapid plasma exposure of SHR7280 may contribute to the quick response of sex hormones. The inhibitory effects on sex hormone were dose-proportional, and higher doses, such as 800, 1000, or even 600 mg BID, achieved medical castration of these hormones [We found that the plasma concentration of SHR7280 was negatively correlated with declining levels of LH, FSH, and testosterone. Exploring the correlation between PK and PD parameters is helpful in guiding the optimal selection of drug dose and frequency in further clinical development since the association between PK and PD parameters represents the relationship between the optimal drug dose and clinical outcomes.The study has several limitations. Firstly, the small sample size met the requirements for a dose-ascending phase 1 trial design but may have introduced bias into the final results. Secondly, efficacy data was not included as only healthy subjects were enrolled. Further evaluation of SHR7280 in larger cohorts of subjects is warranted. Thirdly, the administration period of the study drug was short. Considering that long-term drug castration therapy may cause severe psychological burden to healthy male subjects, we restricted the SHR7280 administration duration to 14 days. Fourthly, the healthy subjects enrolled in this study were younger than the typical age of prostate cancer patients. Elderly subjects are often prescribed more concomitant medications than younger patients, which may introduce bias in the interpretation of the safety, PK, and PD data of SHR7280. Therefore, we do not restrict enrollment to only elderly individuals. Meanwhile, we are conducting another clinical trial of SHR7280 (NCT04995042) to explore the safety, PK, PD, and efficacy of SHR7280 under a longer administration time (administration duration of 1 year) in patients with hormone-sensitive prostate cancer who are older than those in the current study.