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A Signal-Finding Study of Abemaciclib in Heavily Pretreated Patients with Metastatic Castration-Resistant Prostate
Neeraj Agarwal1, Daniel Castellano2, Teresa Alonso-Gordoa3
1Huntsman Cancer Institute, University of Utah (NCI-CCC), Salt Lake City, Utah.
Purpose:
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC).
Patients And Methods:
Eligible patients had progressive mCRPC, measurable disease, and previously received ≥1 novel hormonal agent(s) and 2 lines of taxane chemotherapy. Abemaciclib 200 mg twice daily was administered on a continuous dosing schedule. Primary endpoint was objective response rate (ORR) without concurrent bone progression. This study was designed to detect a minimum ORR of 12.5%.
Results:
At trial entry, 40 (90.9%) of 44 patients had objective radiographic disease progression, 4 (9.1%) had prostate-specific antigen (PSA)-only progression, and 20 (46.5%) had visceral metastases (of these, 60% had liver metastases). Efficacy analyses are as follows: ORR without concurrent bone progression: 6.8%; disease control rate: 45.5%; median time to PSA progression: 6.5 months [95% confidence interval (CI), 3.2-NA]; median radiographic PFS; 2.7 months (95% CI, 1.9-3.7); and median OS, 8.4 months (95% CI, 5.6-12.7). Most frequent grade ≥3 treatment-emergent adverse events (AE) were neutropenia (25.0%), anemia, and fatigue (11.4% each). No grade 4 or 5 AEs were related to abemaciclib.
Conclusions:
Abemaciclib monotherapy was well tolerated and showed clinical activity in this heavily pretreated population, nearly half with visceral metastases. This study is considered preliminary proof-of-concept and designates CDK4/6 as a valid therapeutic target in prostate cancer.
Insights
Abemaciclib, a CDK4/6 inhibitor, demonstrated clinical activity in patients with advanced prostate cancer. This study provides preliminary evidence that targeting CDK4/6 is a viable strategy for treating this difficult-to-treat cancer.
Area of Science:
- Oncology
- Pharmacology
Background:
- Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed breast cancer treatment.
- Androgen receptor signaling in prostate cancer activates cyclin D-CDK4/6, promoting proliferation and resistance to hormonal therapies.
Purpose of the Study:
- To evaluate the clinical activity of abemaciclib in patients with metastatic castration-resistant prostate cancer (mCRPC) refractory to prior treatments.
- To establish CDK4/6 as a therapeutic target in prostate cancer.
Main Methods:
- A phase II study administered abemaciclib 200 mg twice daily to patients with progressive mCRPC who had received prior novel hormonal agents and taxane chemotherapy.
- The primary endpoint was objective response rate (ORR) excluding concurrent bone progression.
Main Results:
- The study included 44 heavily pretreated patients, with 46.5% having visceral metastases.
- The ORR was 6.8%, with a disease control rate of 45.5%. Median time to PSA progression was 6.5 months, and median overall survival was 8.4 months.
- Most common grade ≥3 adverse events included neutropenia (25.0%), anemia, and fatigue. No grade 4 or 5 adverse events were attributed to abemaciclib.
Conclusions:
- Abemaciclib monotherapy was well-tolerated and showed clinical activity in a pretreated mCRPC population, including those with visceral metastases.
- This preliminary proof-of-concept study supports CDK4/6 as a valid therapeutic target in prostate cancer.
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