CYCLONE 1 Misses Primary End Point But Abemaciclib Shows Activity in mCRPC

Although the phase 2 CYCLONE 1 trial (NCT04408924) did not meet its primary end point of overall response rate (ORR), treatment with abemaciclib (Verzenio) did demonstrate clinical activity among patients withmetastatic castration-resistant prostate cancer (mCRPC), according to findings presented during the 2023 AACR Annual Meeting.¹

At the April 27, 2022, data cutoff, at a median follow-up of approximately 8.5 months, results from CYCLONE 1 showed that patients who received the CDK4/6 inhibitor (n = 44) experienced an ORR of 6.8% (95% CI, 0.0%-14.3%), defined as a confirmed soft tissue response without concurrent bone progression.

The disease control rate (DCR) was 45.5% (95% CI, 30.7%-60.2%), with 38.6% of patients achieving stable disease (SD). SD persisted for at least 6 months in 13.6% of patients. All responses were partial, and 20.5% of patients were not evaluable (NE) for response.¹

CYCLONE 1 was a single-arm trial that evaluated the safety and efficacy of abemaciclib monotherapy in patients with mCRPC with an ECOG performance status of 0 or 1 who had received prior treatment with at least 1 novel hormonal agent and 2 prior taxanes for metastatic prostate cancer. Patients who had previously received abemaciclib or another CDK4/6 inhibitor, those with brain metastases, and those who have received more than 3 therapy regimens for mCRPC were excluded from the study.^1,2

Oral abemaciclib was given at a dose of 200 mg twice daily as part of a continuous 28-day dosing schedule until radiographic or symptomatic progression or unacceptable toxicity. The median number of treatment cycles was 3 (range, 1-13).¹

In terms of the primary end point, a target ORR of at least 12.5% was deemed suitable to support further evaluation of abemaciclib monotherapy in the refractory mCRPC setting. Secondary end points included radiographic progression-free survival (rPFS), DCR, overall survival (OS), safety, and time to prostate-specific antigen (PSA) progression.

The median age of patients enrolled on the trial was 68 years (range, 48-94). Most patients had an ECOG performance status of 1 (75%), at least 3 metastatic sites (93.0%), radiographic progression at trial entry (90.9%), and had a nonvisceral disease site (53.5%). Visceral metastasis was reported in 46.5% of patients, including 27.9% with liver metastasis.¹

The median time from development of mCRPC to study entry was 2.1 years. The median number of prior systemic regimens for mCRPC was 3.¹

Most patients (56.8%) underwent at least 3 lines of prior therapy, with 43.2% being treated with 2 or fewer. The most common prior chemotherapy agents included docetaxel (100%), cabazitaxel (90.9%), carboplatin (4.5%), and paclitaxel (2.3%). Previous novel hormonal agents included abiraterone acetate (Zytiga; 54.5%), enzalutamide (Xtandi; 54.5%), apalutamide (Erleada; 4.5%), and darolutamide (Nubeqa; 2.3%). Prior immunotherapy approaches, which 13.6% of patients had overall, included pembrolizumab (Keytruda; 6.8%), atezolizumab (Tecentriq; 2.3%), durvalumab (Imfinzi; 2.3%), ipilimumab (Yervoy; 2.3%), and nivolumab (Opdivo; 2.3%).

At the time of data cutoff, 7% of patients remained on treatment. Among the 41 patients who ceased treatment, reasons for discontinuation included progressive disease (68%), adverse effects (14%), physician’s decision (5%), withdrawal (5%), and death (2%).

Additional data regarding survival outcomes showed that the median rPFS was 2.7 months (95% CI, 1.9-3.7), with a 6-month rPFS rate of 24.9% (95% CI 12.4%-39.5%) and 75% of patients experienced an rPFS event. The median OS was 7.6 months (95% CI 5.6-not estimable [NE]), with 43.2% of patients experiencing an OS event. The duration of response ranged from 3.7 months to 5.6 months.

The median time to PSA progression was 6.5 months (95% CI, 3.2-NE), with 29.5% of patients experiencing a PSA progression event. Any PSA decrease was reported in 27.3% of patients and 4.6% experienced a confirmed PSA response rate of at least 50%. The median time to systemic progression was 4.1 months (95% CI, 3.7-NE).¹

The safety profile of abemaciclib was consistent with what has been previously observed in patients with breast cancer, investigators noted. The most common any-grade treatment-related adverse effects (TRAEs) of any grade included diarrhea (79.5%), decreased appetite (52.3%), and fatigue (50%). Most of these events were grade 1 or 2 in severity.¹

Grade 3 TRAEs consisted of neutropenia (22.7%), anemia (6.8%), fatigue (6.8%) and diarrhea (6.8%). Grade 4 or 5 TRAEs were not reported and the discontinuation rate due to AEs was 13.6%.¹

Treatment-emergent adverse events (TEAEs) of any grade included diarrhea (81.8%), fatigue (63.6%), decreased appetite (54.5%), and nausea (47.7%). Grade 3 TEAEs consisted of neutropenia (25.0%), fatigue (11.4%), diarrhea (9.1%), and thrombocytopenia (4.5%).

Study authors concluded that the single-agent activity displayed by abemaciclib in CYCLONE 1 validates CDK4/6 as a therapeutic target in advanced prostate cancer. The phase 2/3 CYCLONE 2 (NCT03706365) and the phase 3 CYCLONE 3 (NCT05288166) trials are underway, examining abemaciclib in combination with abiraterone acetate and prednisone for patients with treatment-naïve mCRPC and high-risk metastatic hormone-sensitive prostate cancer, respectively.¹

References

1. Agarwal N, Gauna DC, Gordoa TA, et al. CYCLONE 1: abemaciclib in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Cancer Res. 2023;83(suppl 8):CT159. doi:10.1158/1538-7445.AM2023-CT159
2. Abemaciclib (LY2835219) in men with heavily treated metastatic castration-resistant prostate cancer (CYCLONE 1). ClinicalTrials.gov. Updated February 14, 2023. Accessed April 17, 2023. https://clinicaltrials.gov/ct2/show/NCT04408924