A Phase Ib/II Study of the CDK4/6 Inhibitor Ribociclib in Combination with Docetaxel plus Prednisone in Metastatic Castration-Resistant Prostate Cancer

Abstract

Purpose: Ribociclib, a CDK4/6 inhibitor, demonstrates preclinical antitumor activity in combination with taxanes. We evaluated the safety and efficacy of ribociclib plus docetaxel in a phase Ib/II study in metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods: Patients had chemotherapy-naïve mCRPC with progression on ≥ 1 androgen receptor signaling inhibitor (ARSI). The phase II primary endpoint was 6-month radiographic progression-free survival (rPFS) rate, with an alternative hypothesis of 55% versus 35% historical control. Circulating tumor cells (CTC) were collected at baseline and genomically profiled. Result: Forty-three patients were enrolled (N = 30 in phase II). Two dose-limiting toxicities were observed (grade 4 neutropenia and febrile neutropenia). The recommended phase II dose (RP2D) and schedule was docetaxel 60 mg/m2 every 21 days plus ribociclib 400 mg/day on days 1–4 and 8–15 with filgrastim on days 5–7. At the RP2D, neutropenia was the most common grade ≥ 3 adverse event (37%); however, no cases of febrile neutropenia were observed. The primary endpoint was met; the 6-month rPFS rate was 65.8% [95% confidence interval (CI): 50.6%–85.5%; P = 0.005] and median rPFS was 8.1 months (95% CI, 6.0–10.0 months). Thirty-two percent of evaluable patients achieved a PSA50 response. Nonamplified MYC in baseline CTCs was associated with longer rPFS (P = 0.052). Conclusions: The combination of intermittent ribociclib plus every-3-weeks docetaxel demonstrated acceptable toxicity and encouraging efficacy in ARSI-pretreated mCRPC. Genomic profiling of CTCs may enrich for those most likely to derive benefit. Further evaluation in a randomized clinical trial is warranted.

ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer

“…The E2F/RB module is a key transcriptional regulator of many genes required for G1/S transition (49). Unfortunately, RB1 gene alterations that inactivates its function to regulate E2Fs are commonly found in a vast majority of human tumors, including NEPC (1,50). Therefore, it is important to find alternative modes that control E2F signaling and cell cycle progression.…”

Extensive germline-somatic interplay contributes to prostate cancer progression through HNF1B co-option of TMPRSS2-ERG

“…It is noteworthy that uncontrolled cell growth and division are a cardinal feature of cancer cells 84 , and accordingly, many inhibitory drugs have been developed in clinical use to target cell cycle progression for cancer therapy 85 . For example, CDK4/6 inhibitors targeted the G1/S phase cell-cycle pathway were recently applied and evaluated in the clinical trial for advanced PCa 86 . Here we show that risk genotypes of the 17q12 PCa risk SNPs are associated with an elevated expression of HNF1B, thereby contributing to PCa cell proliferation and tumor progression.…”

Small molecule inhibitors targeting the cancers

“… 410 , 411 Phase II trial of ribociclib in combination with docetaxel plus prednisone had acceptable toxicity and encouraging efficacy in metastatic castration‐resistant prostate cancer. 412 Abemaciclib even showed promising clinical activity in patients with p16ink4A‐deficient mesothelioma in a single‐arm phase II trial (NCT03654833). 413 These inhibitors are ongoing clinical trials for ovarian cancer, NSCLC, RCC, AML, and so on (NCT03936270, NCT03170206, NCT05468697, and NCT03844997).…”

“…Phase II trials supported the use of this agent in HPV‐unrelated HNSCC and liposarcoma (NCT02101034 and NCT01209598) 410,411 . Phase II trial of ribociclib in combination with docetaxel plus prednisone had acceptable toxicity and encouraging efficacy in metastatic castration‐resistant prostate cancer 412 . Abemaciclib even showed promising clinical activity in patients with p16ink4A‐deficient mesothelioma in a single‐arm phase II trial (NCT03654833) 413 .…”