ASCO 2022: A Phase 3 Trial of SHR3680 Versus Bicalutamide in Combination With ADT in Patients With High-Volume mHSPC

(UroToday.com) The 2022 ASCO annual meeting featured an oral abstract session on prostate cancer, including a presentation by Dr. Ding-Wei Ye discussing the phase 3 trial of SHR3680 versus bicalutamide in combination with ADT in patients with high-volume mHSPC. Dr. Ye notes that prostate cancer accounts for about 1.4 million new diagnoses and 375,000 deaths worldwide. Furthermore, prostate cancer is the second most frequently diagnosed cancer and the fifth leading cause of cancer-related death among men in 2020. Both TITAN1 and ARCHES2 studies have demonstrated significant clinical benefits of second-generation androgen receptor inhibitors plus ADT versus placebo plus ADT in the treatment of mHSPC. As follows are the key clinical trials in mHSPC:

 

ASCO 2022_Ding-Wei Ye_0 

 

However, first-generation androgen receptor inhibitors plus ADT is also widely used in clinic and how superior second-generation androgen receptor inhibitors is to first-generation ones remains to be determined. The CHART study evaluated the efficacy and safety of SHR3680, a novel oral androgen receptor inhibitor, versus bicalutamide in high-volume mHSPC.

 CHART is a randomized, open-label, phase 3 study (NCT03520478). Patients with mHSPC were randomized 1:1 to ADT plus either SHR3680 (240 mg/d) or bicalutamide (50 mg/d). All patients had high-volume disease adapted from the CHAARTED study. The study design for CHART is as follows:

 

ASCO 2022_Ding-Wei Ye_1 

 

The primary endpoints were radiographic progression-free survival (rPFS) assessed by independent review committee (IRC) and overall survival (OS). The study had 95% power with 282 rPFS events at an alpha of 0.05 and a hazard ratio of 0.65. The study also had 89% power with 325 OS events at an alpha of 0.05 and a hazard ratio of 0.70. As of May 16, 2021, 209 rPFS events per IRC and 153 deaths occurred and a preplanned interim analysis for rPFS was undertaken.

 There were 654 patients randomized to receive SHR3680 (n = 326) or bicalutamide (n = 328), with 191 patients still receiving SHR3580 and 60 patients still receiving bicalutamide. The baseline characteristics for both groups are as follows:

 

ASCO 2022_Ding-Wei Ye_2 

 

At data cutoff, the median follow-up duration was 22.1 months in SHR3680 group and 20.4 months in bicalutamide group. SHR3680 significantly reduced the risk of radiographic progression or death than bicalutamide (HR 0.44, 95% CI 0.33-0.58; p < 0.0001; median, not reached vs 25.1 months):

 

ASCO 2022_Ding-Wei Ye_3 

 

OS data were immature but an improved OS was observed in SHR3680 group (median not reached) compared to bicalutamide group (median not reached; HR 0.58, 95% CI 0.42-0.80; p = 0.0009):

 

ASCO 2022_Ding-Wei Ye_4 

 

Updated IRC-assessed rPFS (data cutoff February 28, 2022) continued to show a benefit for SHR3680 (HR 0.46, 95% CI 0.36-0.60):

 

ASCO 2022_Ding-Wei Ye_5 

 

Subgroup analyses for rPFS all generally favored SHR3680:

 

ASCO 2022_Ding-Wei Ye_6 

 

All secondary efficacy endpoints favored SHR3680 plus ADT:

  • Investigator-assessed rPFS: HR 0.39, 95% CI 0.30-0.50
  • Time to PSA progression: HR 0.21, 95% CI 0.16-0.27
  • Time to next skeletal related event: HR 0.65, 95% CI 0.50-0.84
  • Time to new anti-prostate cancer therapy: HR 0.33, 95% CI 0.26-0.41

 

ASCO 2022_Ding-Wei Ye_7 

 

 

Frequencies of adverse events of any cause in any grade were similar between groups. Grade ≥3 treatment-related adverse events occurred in 19.2% and 13.9% of patients in SHR3680 and bicalutamide groups, respectively. No seizures occurred in SHR3680 group.

 

Dr. Ye concluded this presentation by discussing the phase 3 trial of SHR3680 versus bicalutamide in combination with ADT in patients with high-volume mHSPC with the following take-home messages:

  • SHR3680 plus ADT significantly improved rPFS versus bicalutamide plus ADT in patients with high-volume mHSPC
  • SHR3680 plus ADT also significantly improved OS versus bicalutamide plus ADT
  • SHR3680 plus ADT showed a desirable safety profile
  • These data support SHR3680 plus ADT as a standard therapy for mHSPC

 

Presented by: Ding-Wei Ye, MD, PhD, Fudan University Shanghai Cancer Center, Shanghai, China

Co-Authors: Weijie Gu, Weiqing Han, Hong Luo, Fangjian Zhou, Dalin He, Lulin Ma, Hongqian Guo, Chaozhao Liang, Tie Chong, Jun Jiang, Zhiwen Chen, Yong Wang, Qing Zou, Ye Tian, Jun Xiao, Jian Huang, Xinfeng Yang, Junliang Li, Chunlei Jin

Affiliations: The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Center, Changsha, China, Chongqing University Cancer Hospital, Chongqing Cancer Hospital, Chongqing, China, Sun Yat-Sen University Cancer Center, Guangzhou, China, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China, Peking University Third Hospital, Beijing, China, Nanjing Drum Tower Hospital, Nanjing, China, First Affiliated Hospital of Anhui Medical University, Hefei, China, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi'an, China, Daping Hospital of Army Medical University, Chongqing, China, The Southwest Hospital of Army Medical University, Chongqing, China, The Second Hospital of Tianjin Medical University, Tianjin, China, Jiangsu Cancer Hospital, Nanjing, China, Beijing Friendly Hospital of Capital Medical University, Beijing, China, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, Hefei, China, Sun Yat-Sen Memorial Hospital Sun Yat-Sen University, Guangzhou, China, Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China, Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China

 

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022. 

References:

  1. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med 2019 Jul 4;381(1):13-24.
  2. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy with Enzalutamide or Placebo in Men with Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2019 Nov 10;37(32):2974-2986.

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