mCRPC in focus
Transcript: CYCLONE-2 reveals subgroup benefits
Dr Alexander Chehrazi-Raffle
Interview recorded June 2024. All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
CYCLONE 2 is a phase 3 study that looked at abemaciclib with abiraterone in patients with mCRPC. AR signalling activates CDK46 to sustain proliferation of prostate cells and cyclin D1 has been implicated as a potential mediator of resistance to ARPIs. CYCLONE 1 was a phase 2 study of abemaciclib monotherapy in mCRPC that was presented at the 2023 AACR conference. Although it missed its primary endpoint, it did show some promising signals of efficacy with a disease control rate of about 45%. So CYCLONE 2 was a phase 2/3 study in ARPI naive patients with mCRPC. Patients were randomised abiraterone plus abemaciclib versus abiraterone plus placebo, and the primary endpoint was RPFS and the intention to treat population.
Baseline characteristics between the two cohorts were pretty balanced, including approximately one third of patients having received docetaxel in a hormone sensitive setting in both arms. Unfortunately, the addition of abemaciclib did not significantly approve rPFS. The combination arm achieved a median rPFS of about 22 months versus 20 months in the placebo arm, which equated to a hazard ratio of about 0.8. That was not statistically significant. Median overall survival was 38 versus 33 months. Also not significant. PSA 50 and PSA 90 were both comparable between the two arms at about 70 and 45% respectively. When looking at subgroups, it showed that there was potentially a greater effect in patients with higher risk disease, such as high baseline PSA and M1 disease at diagnosis. Toxicity was high in the combination arm with expected toxicities as seen from patients with hormone receptor positive breast cancer, where abemaciclib is approved. So things like diarrhoea, cytopenias, and hepatotoxicity were more common. We'll have to await CYCLONE-3 to see if biological activity of the combination is more active in this high risk metastatic hormone sensitive setting. But given the results of CYCLONE-2, I don't anticipate there to be any new signals of efficacy in the hormone sensitive setting.
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