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The combination of the CDK4/6 inhibitor ribociclib (Kisqali) plus docetaxel and prednisone showed promising clinical activity with a tolerable safety profile in patients with metastatic castration-resistant prostate cancer (mCRPC), according to findings from a phase 1b/2 trial shared during the 2021 ASCO Annual Meeting.1
The 6-month radiographic progression-free survival (rPFS) with the ribociclib regimen was 65% and the median rPFS was 8.1 months. Among patients who were treated with the recommended phase 2 dose (RP2D), 27% had a PSA decline from baseline of ≥50%.
Explaining the rationale for the trial, first study author Ivan De Kouchkovsky, MD, a medical oncology fellow at the University of California, San Francisco, said, “We know that taxanes are a cornerstone of the treatment for patients with mCRPC; however, the survival benefit from docetaxel is modest. There is preclinical and now some emerging clinical data to suggest that CDK4/6 inhibitors, such as ribociclib, may have synergistic activity with taxanes. And so, we sought to determine the safety and efficacy of the combination of ribociclib with docetaxel in patients with mCRPC.”
The study enrolled patients with mCRPC who had measurable or nonmeasurable disease. Patients had to have progressed on ≥1 androgen receptor signaling inhibitor. Prior docetaxel in the mCRPC setting was not allowed.
Overall, 43 patients were enrolled in the trial between November 2015 and June 2019. The median patient age was 68 years (range, 55-84). Thirty-three percent (n =14) of patients had a Gleason Score ≤7, 58% (n = 25) of patients had a Gleason Score >7, and the Gleason score was unknown for 9% (n = 4) of patients. Sixty percent (n = 26) of patients had an ECOG score of 0 and 40% (n = 17) had and ECOG score of 1. About one-fourth (23%) of patients had visceral metastases.
The RP2D was determined to be ribociclib at 400 mg/daily plus docetaxel at 60 mg/m2 and prednisone at 5 mg twice daily. Patients received the regimen for a maximum of 9 cycles. Patients reaching stable disease or better following 9 cycles then received maintenance ribociclib and treatment continued until disease progression.
Among the 30 patients who received the RP2D, the most common treatment-related adverse events (TRAEs) were fatigue (63.3%; n = 19), nausea (50%; n = 15), neutropenia (43.3% n = 13), alopecia (43.3%; n = 13), dysgeusia (33.3%; n = 10), neuropathy (30%; n = 9), diarrhea (26.7%; n = 8), anemia (26.7%; n = 8), lymphocytopenia (10% n = 3).
Grade ≥3 TRAEs included neutropenia (n = 11), lymphocytopenia (n = 3), and 1 case each of fatigue, nausea, diarrhea, and anemia. Of note, there were no reported cases of febrile neutropenia of any grade at the RP2D.
Ribociclib currently has approved FDA indications for the treatment of patients with breast cancer.
1. De Kouchkovsky I, Rao A, Carneiro BA. A phase (Ph) 1b/2 study of ribociclib (R) in combination with docetaxel (D) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 39, 2021 (suppl 15; abstr 5043). doi: 10.1200/JCO.2021.39.15_suppl.5043