P-VERIFY: Real-World Comparative Overall Survival and Progression-Free Survival of CDK4/6 Inhibitors Plus an Aromatase Inhibitor in Patients with HR+/HER2− Metastatic Breast Cancer in the USA—A Vodcast

Abstract

To date, there have been no head-to-head randomized controlled trial data comparing cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in patients with HR+/HER2− metastatic breast cancer (mBC), and most prior real-world comparative effectiveness studies have been limited by short follow-up times and small patient sample sizes. In this vodcast, we provide an overview of two recent publications reporting overall survival (OS) and real-world progression-free survival (rwPFS) results from P-VERIFY, a retrospective comparative effectiveness study of CDK4/6 inhibitors plus an aromatase inhibitor (AI) among patients with HR+/HER2− mBC treated in routine clinical practice in the USA. P-VERIFY used the Flatiron Health Analytic Database to identify 9146 patients who initiated first-line (1L) treatment with palbociclib (n = 6831), ribociclib (n = 1279), or abemaciclib (n = 1036), plus an AI, between February 2015 and November 2023. In primary analyses, there were no significant differences in OS and rwPFS between treatment groups after stabilized inverse probability treatment weighting, with hazard ratios ranging from 0.95 to 0.98 across pairwise group comparisons (all P > 0.05). Findings remained generally consistent across sensitivity and subgroup analyses and in a subanalysis of patients who started treatment in 2017 or later, when all three CDK4/6 inhibitors were commercially available. Taken together, results from P-VERIFY, the largest real-world study to date evaluating CDK4/6 inhibitor comparative effectiveness, suggest that there are no significant differences in OS and rwPFS between 1L palbociclib, ribociclib, and abemaciclib, plus an AI, in patients with HR+/HER2− mBC in US routine clinical practice.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s11523-026-01233-0.

Key Points

The P-VERIFY study compared the effectiveness of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (palbociclib, ribociclib, and abemaciclib) when used in combination with an aromatase inhibitor as first-line treatment for patients with HR+/HER2− metastatic breast cancer in routine clinical practice in the USA.

This vodcast describes two recent publications reporting overall survival (OS) and real-world progression-free survival (rwPFS) results from the P-VERIFY study.

Taken together, these results from P-VERIFY showed no significant differences in OS and rwPFS between CDK4/6 inhibitors.

Infographic

The vodcast and transcript can be viewed below the abstract of the online version of the article. The slide deck is included as an Electronic Supplementary File with the online version of the article. Alternatively, the vodcast and slide deck can be downloaded here: https://doi.org/10.6084/m9.figshare.32745462.

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Vodcast Transcript

Hello, and welcome to this vodcast on the P-VERIFY study. My name is Hope Rugo; I am a professor of medical oncology and therapeutics research, as well as director of the Women’s Cancers Program and chief of the Division of Breast Medical Oncology at the City of Hope Comprehensive Cancer Center. On behalf of my coauthors, I am pleased to provide an overview of our two recent publications reporting overall survival and real-world progression-free survival results from P-VERIFY, a real-world study comparing the effectiveness of CDK4/6 inhibitors plus an aromatase inhibitor in patients with HR+/HER2− metastatic breast cancer. Beyond the information presented in this vodcast, additional details about the P-VERIFY study can be found in the two original articles, both published in ESMO Open in 2025, the first reporting overall survival results [1] and the second reporting real-world progression-free survival results [2].

Treatment with a CDK4/6 inhibitor combined with endocrine therapy is a standard-of-care, first-line regimen for patients with HR+/HER2– metastatic breast cancer [3, 4]. In 2015, palbociclib was the first CDK4/6 inhibitor approved in the USA, later followed by the approvals of ribociclib and abemaciclib in 2017 [5–7]. The efficacy of the combination of a CDK4/6 inhibitor plus an aromatase inhibitor, or AI, as first-line treatment of HR+/HER2– metastatic breast cancer was established in randomized controlled trials, including the PALOMA-2 trial evaluating palbociclib, the MONARCH-3 trial evaluating abemaciclib, and the MONALEESA-2 trial evaluating ribociclib [8–10]. In each of these trials, first-line treatment with a CDK4/6 inhibitor plus an AI significantly prolonged progression-free survival, the primary endpoint, compared with placebo plus AI. Although all three CDK4/6 inhibitors numerically prolonged overall survival, only ribociclib plus AI demonstrated statistically significant prolongation of overall survival when compared with placebo plus AI [11–13].

Randomized controlled trials are the gold standard for evaluating drug safety and efficacy; however, the generalizability of clinical trial results and their applicability to real-world patients can be limited due to stringent eligibility criteria and relatively small patient sample sizes [14, 15]. To fill this gap in knowledge, real-world evidence derived from studies evaluating treatment outcomes in large and heterogeneous real-world patient populations can complement clinical trial data in informing clinical practice [15–17].

In the absence of head-to-head randomized controlled trial data, several real-world studies have evaluated the comparative effectiveness of the three approved CDK4/6 inhibitors [18–27]. Findings were inconsistent across these studies, although most did not show significant differences in overall survival or real-world progression-free survival. However, these studies were limited by short follow-up times and small patient sample sizes. Therefore, larger real-world studies with longer follow-up are needed to further characterize the comparative effectiveness of CDK4/6 inhibitors.

P-VERIFY was a retrospective comparative effectiveness study of CDK4/6 inhibitors in combination with an AI as first-line treatment for patients with HR+/HER2− metastatic breast cancer in routine clinical practice in the USA. P-VERIFY used the deidentified longitudinal Flatiron Health Analytic Database, derived from electronic health records from over 280 cancer clinics across the USA. Representing the largest real-world study to date of the comparative effectiveness of CDK4/6 inhibitors, P-VERIFY included 9146 patients with HR+/HER2− metastatic breast cancer who initiated first-line treatment with a CDK4/6 inhibitor plus an AI between February 2015 and November 2023. A total of 6831 patients received palbociclib plus an AI, 1279 received ribociclib plus an AI, and 1036 received abemaciclib plus an AI. Patients were followed from the start of treatment with a CDK4/6 inhibitor plus an AI until their last medical activity, death, or the data cutoff date of 31 May 2024, whichever came first.

In the analyses presented here, we compared overall survival and the real-world progression-free survival in patients receiving palbociclib, ribociclib, or abemaciclib in combination with an AI. Overall survival was defined as the time from the start of CDK4/6 inhibitor plus AI treatment until death. Real-world progression-free survival was defined as the number of months from the start of index treatment to disease progression or death from any cause, whichever occurred first. We employed three different methods for comparative analysis including an unadjusted analysis; the primary analysis using stabilized inverse probability of treatment weighting, or sIPTW; and a sensitivity analysis using a multivariable Cox proportional hazards model.

Since P-VERIFY was a nonrandomized retrospective database analysis, sIPTW was implemented to balance baseline characteristics between treatment groups. Before sIPTW, there were some differences between the treatment groups; for example, the median age in the palbociclib group was 2 years older than the other treatment groups, and the abemaciclib group had a higher proportion of patients with visceral metastases. After sIPTW, baseline demographics and clinical characteristics were generally balanced between treatment groups. In each cohort after sIPTW, the median age was 66 years, 1% of patients were male, and 37% were non-White. Roughly 85% of patients were treated in the community practice setting. In each cohort after sIPTW, approximately 35% of patients had visceral metastases and 46% had bone-only metastases. After sIPTW, 4% of patients in each cohort had a disease-free interval of 1 year or less, 16% had a disease-free interval between 1 and 5 years, and 30% had a disease-free interval greater than 5 years.

Focusing first on the results from the primary analysis after sIPTW, the median follow-up duration after sIPTW was 21.5 months in the abemaciclib group, 15.7 months in the ribociclib group, and 33.0 months in the palbociclib group. Overall, we found no significant differences in overall survival between treatment groups after sIPTW. The hazard ratio was 0.95 when comparing the abemaciclib and palbociclib groups, 0.98 when comparing the ribociclib and palbociclib groups, and 0.97 when comparing the abemaciclib and ribociclib groups. The P-value was greater than 0.05 for each of these comparisons.

After sIPTW, landmark overall survival rates were similar across treatment groups, ranging from 88% to 90% at 12 months, 76% to 78% at 24 months, and 71% to 72% at 30 months. Median overall survival after sIPTW was 64.5 months in the abemaciclib group, 59.0 months in the ribociclib group, and 54.6 months in the palbociclib group. Notably, point estimates of overall survival, including the median, were not stable beyond the 30-month time point due to the small numbers of patients remaining at risk in the ribociclib and abemaciclib treatment groups. This highlights the importance of focusing on the hazard ratio when performing a time-to-event comparative analysis rather than a descriptive statistic at a single time point, such as the median.

In an exploratory analysis, we also evaluated overall survival after sIPTW in subgroups separated by various baseline demographics or clinical characteristics. Across patient subgroups by age, race, practice setting, or disease stage at initial diagnosis, results were generally consistent with those from the overall cohort for each pairwise group comparison. For each treatment comparison, results also remained generally consistent across subgroups by performance status; disease-free interval; visceral or bone-only disease status; or number of metastatic sites.

Similar to the primary analysis, there were no significant differences in overall survival between treatment groups in the unadjusted analysis. The hazard ratio was 0.94 for the abemaciclib versus palbociclib pairwise group comparison, 0.93 for ribociclib versus palbociclib, and 1.01 for abemaciclib versus ribociclib. Consistent with the primary analysis after sIPTW, unadjusted overall survival rates were similar in the palbociclib, ribociclib, and abemaciclib treatment groups at 12, 24, and 30 months. Results were generally consistent in a sensitivity analysis using a multivariable Cox proportional hazards model.

A subanalysis of patients who began treatment in 2017 or later was also performed to focus on comparative overall survival after all three CDK4/6 inhibitors became commercially available in the USA, following the approval of palbociclib in 2015 and ribociclib and abemaciclib in 2017 [5–7]. Overall, results consistent with the total study population were observed. After sIPTW, there were no significant differences in overall survival between treatment groups, with hazard ratios ranging from 0.96 to 1.0 and with all P-values greater than 0.05. In addition, overall survival rates were similar across treatment groups at 12, 24, and 30 months.

Beyond overall survival, we also compared real-world progression-free survival between treatment groups. After sIPTW, there were no significant differences in real-world progression-free survival between treatment groups, with a hazard ratio of 0.96 for abemaciclib versus palbociclib, 0.97 for ribociclib versus palbociclib, and 0.98 for abemaciclib versus ribociclib. The P-value was greater than 0.05 for each of these comparisons.

We further evaluated real-world progression-free survival after sIPTW in exploratory subgroup analyses. For each treatment group comparison, results in subgroups by age, race, practice setting, or disease stage at initial diagnosis were generally consistent with those reported in the overall patient cohort. Similarly, findings remained generally consistent when pairwise group comparisons were performed in subgroups by performance status, disease-free interval, visceral or bone-only disease status, or number of metastatic sites.

Similar to the primary analysis after sIPTW, the unadjusted analysis found no significant differences in real-world progression-free survival between treatment groups. The hazard ratio was 0.99 for the abemaciclib versus palbociclib pairwise group comparison, 0.97 for ribociclib versus palbociclib, and 1.02 for abemaciclib versus ribociclib. The P-value was greater than 0.05 for each of these comparisons. Real-world progression-free survival also did not vary significantly between treatment groups in a sensitivity analysis using a multivariable Cox proportional hazards model, with hazard ratios ranging from 0.96 to 1.02 and with all P-values greater than 0.05.

Lastly, results consistent with the total study population were observed in the subanalysis of patients who started index treatment in 2017 or later. After sIPTW, there were no significant differences in real-world progression-free survival between treatment groups, with hazard ratios ranging from 0.96 to 0.98 and with all P-values greater than 0.05.

The P-VERIFY study has several strengths, including its large sample size of 9146 patients to evaluate the comparative effectiveness of CDK4/6 inhibitors. P-VERIFY used the large, nationwide Flatiron Health Analytic Database, which captured comprehensive and longitudinal data from a geographically and demographically diverse set of patients treated in routine clinical practice in the USA. In the Flatiron Health Analytic Database, date of death was a consensus endpoint derived from multiple data sources and validated against the National Death Index. In addition, the findings from the primary analyses were supported by sensitivity and subgroup analyses.

Limitations of P-VERIFY include its retrospective observational design, which carries an inherent risk of treatment selection bias and collection of incomplete or inaccurate data. No causal relationships could be made. Due to the nonrandomized study design, sIPTW and multivariable regression were utilized, which could not account for potential unmeasured covariates. Disease progression was based on treating physicians’ clinical assessments or interpretation of radiology or pathology results, rather than standard criteria. The ribociclib and abemaciclib treatment groups had small sample sizes and short follow-up times compared with the palbociclib group. Findings from P-VERIFY may not be generalizable to patient populations that were not represented in the Flatiron Health Analytic Database. Lastly, it is important to remember that P-VERIFY is a single study that should be considered in conjunction with the totality of data across randomized controlled trials and real-world studies evaluating CDK4/6 inhibitor plus AI treatment in patients with HR+/HER2− metastatic breast cancer.

In conclusion, P-VERIFY is the largest real-world study conducted to date evaluating the comparative effectiveness of CDK4/6 inhibitors in combination with AI. The results from P-VERIFY suggest that there are no significant differences in overall survival and real-world progression-free survival between palbociclib, ribociclib, and abemaciclib when used in combination with an AI as first-line treatment for patients with HR+/HER2– metastatic breast cancer in routine clinical practice in the USA. To further understand the comparative effectiveness of the three CDK4/6 inhibitors, it would be important to study other treatment outcomes, such as time from the start of first-line index treatment to progression on second-line therapy, duration of treatment, safety, and patient-reported outcomes in the real-world setting.

Thank you very much.

Supplementary Information

Below is the link to the electronic supplementary material.

Funding

This vodcast was supported by Pfizer Inc.

Declarations

Conflicts of Interest

Hope S. Rugo reports a consulting or advisory role for Napo, Bristol Myers Squibb, Helsinn, and BioNTech; institutional research funding to her prior institution (UCSF) from AstraZeneca, Gilead Sciences Inc., Lilly, Merck & Co., Daiichi Sankyo Inc., Novartis Pharmaceuticals, Pfizer Inc., F. Hoffman-La Roche/AG/Genentech, Stemline Therapeutics, and Ambryx; and institutional research funding to City of Hope from Bicycle Therapeutics, F. Hoffman-La Roche/AG/Genentech, Merck, PhoenixMD, and Stemline Therapeutics. Joanne C. Ryan is an employee of and stockholder in Pfizer Inc.

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Author Contributions

The authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.