A systematic review of health-related quality of life outcomes in patients with advanced breast cancer treated with palbociclib

Health related quality of life (HRQoL) is increasingly being acknowledged as an important element in assessing how anticancer therapies influence patient outcomes [1]. HRQoL refers to the patients' own cognitive, physical, emotional and social functioning and symptoms, which are measured using validated tools for collecting patient-reported outcomes (PROs) [2]. Due to its recognized importance to patients, optimizing HRQoL has become a primary goal of breast cancer therapy, alongside prolonging survival and managing symptoms, particularly in the advanced setting where outcomes are often poor [3,4]. In both drug evaluation processes by agencies such as the US FDA and cost–effectiveness analyses in support of healthcare resource allocation, HRQoL has become an accepted parameter to include alongside clinical end points [2,5,6]. In addition to global HRQoL, physical functioning and prominent symptoms such as pain and fatigue, are identified as clinically meaningful outcomes for cancer patients [7–9].

Hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) constitutes the most common breast cancer subtype. Standard of care for treating patients with advanced disease involves the use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with endocrine therapy (ET) [4]. Palbociclib, a first-in-class CDK4/6 inhibitor, received approval for the treatment of HR+/HER2- advanced breast cancer (aBC) or metastatic breast cancer (mBC) from the US FDA in 2015 [10]. To date, several phase III randomized controlled trials (RCTs) [11–13] have demonstrated that palbociclib treatment not only demonstrated a clinical benefit, but also improved or preserved HRQoL in patients with HR+/HER2- aBC compared with the placebo group. Additionally, several real-world evidence (RWE) studies conducted across a variety of countries and patient subgroups have demonstrated consistent results, with HRQoL maintained or enhanced in comparison to baseline values [14–16]. These results are noteworthy as often in the oncology setting, enhanced clinical efficacy typically comes at the cost of additional toxicity, which can negatively impact patient HRQoL [17]. Consistency of findings across trials and real world are encouraging as RWE studies allow for the inclusion of a more diverse patient population compared with clinical trials, and thus may be more representative of the true population in clinical practice [18,19].

The number and variety of studies available, along with the significant heterogeneity between HRQoL instruments, scales and analysis methods, make it challenging to assess the overall impact of palbociclib on a patients' quality of life [20]. Therefore, it is important to understand the totality of HRQoL data for palbociclib in this population. While a recent systematic review indicated that CDK4/6 inhibitors overall generally maintained HRQoL in breast cancer patients of any stage, the systematic assessment of palbociclib on HRQoL in aBC patients within clinical trials and real-world data has not been conducted [21]. Therefore, we aimed to answer what is the impact of palbociclib treatment on HRQoL in patients with HR+/HER2- aBC or mBC in both the clinical and real-world setting. To bridge this knowledge gap, we conducted a systematic literature review (SLR) to identify and summarize all the publicly available evidence pertaining to HRQoL in patients with HR+/HER2- aBC or mBC treated with the CDK4/6 inhibitor palbociclib, thereby providing the most informed evidence base on this subject.

This SLR follows best practices for implementation and reporting in accordance with the Preferred Reporting Items for Systematic Literature Reviews and Meta Analyses (PRISMA) statement [22] (Appendix Table A1). The structure of the clinical question and eligibility criteria, as well as the search strategy were developed using the Population, Intervention, Comparator, Outcome, Study Design (PICOS) framework [23]. The review protocol was designed in alignment with the PRISMA for systematic review protocols (PRISMA-P) statement and was registered with the international prospective register of systematic reviews (PROSPERO; registration no. CRD42023442447) [24].

Patient reported outcomes (PRO) and HRQoL have become an increasingly important complement to efficacy end points in assessing the value of treatments, including treatments for breast cancer [4,65]. PRO data provide important information on how patients feel and function as a result of their disease and treatment; treatment approval and reimbursement decisions often take HRQoL and PRO data into account [2,5,6]. In fact, the FDA is required to make a brief public statement about the patient experience data and related information, such as HRQoL, that is submitted and reviewed as part of all approved drug and biologic marketing applications, according to section 3001 of the 21st Century Cures Act of 2016 [66]. Therefore, it is essential to evaluate HRQoL in clinical practice, particularly in the case of patients with advanced disease, where survival rates are low [4,67].

CDK 4/6 inhibitors in combination with endocrine therapy, introduced in 2015 for the treatment and management of patients with aBC or mBC, are considered an important advancement, with palbociclib being the first in class to attain FDA approval [4,68]. To our knowledge, this is the first systematic review to synthesize the available evidence on HRQoL specifically in patients with HR+/HER2- aBC or mBC treated with palbociclib. The present review not only summarizes the available HRQoL data between palbociclib and comparison groups within RCTs, but also change from baseline (CFB) results among patients treated with palbociclib for all study types, allowing for a wholistic view of results across RCTs, single-arm trials and RWE studies. In addition to global or overall HRQoL, individual findings of key parameters important to patients and physicians were also highlighted, such as physical functioning, pain and fatigue.

Evaluation of global QoL measures in RCTs between groups across instruments (QLQ-C30, EQ-5D, FACT-B/FACT-G) were generally found to be comparable or better in the palbociclib arm compared with the control group, in both the first line setting and beyond. One exception was observed in FLIPPER, where QLQ-C30 global QoL scores for palbociclib examined as a first line therapy were significantly worse than the placebo group; however, differences between groups were due to improvements in the placebo group, while scores were maintained from baseline in the palbociclib group [31]. Worse appetite, constipation and systemic therapy side effects with palbociclib compared with the placebo group were suspected to contribute to these differences in global QoL [31]. Potential reasoning for the improved HRQoL scores observed in the placebo group from baseline was not directly discussed by the authors, but could be related to differences in population, assessments, or external factors. These findings are further supported by the scores for the major palbociclib clinical trials using the European Society for Medical Oncology's Magnitude of Clinical Benefit Scale (ESMO-MCBS), considered to be a robust validated tool for evaluating the clinical benefit of oncology treatments [69,70]. Key RCTs evaluating palbociclib, PALOMA-1, PALOMA-2 and PALOMA-3 included in this review, received ESMO-MCBS scores of 3, 3 and 4, respectively, out of 5 [70]. PALOMA-3 in particular, was initially assigned a score of 3 due to notable benefits in progression-free survival [71]. Nonetheless, the final score was increased to 4 after adjusting for QoL, reflecting the reported delays in deterioration of global QoL in the trial [71]. Results from this review in addition to the ESMO-MCBS scores, demonstrate that palbociclib contributes to improved clinical outcomes, while also maintaining QoL.

CFB results of global QoL were also largely found to be improved or maintained from baseline among patients treated with palbociclib across RCTs, single-arm and RWE studies, instruments (QLQ-C30, EQ-5D, FACT-B/FACT-G) and line of therapy. Although FACT-B total score was observed to be worse than baseline among Asian patients treated with palbociclib in PALOMA-4 [61], these results were in contrast to findings in international patients in PALOMA-2 [33] and a single-arm trial on Japanese patients that found FACT-B results to be maintained, all evaluating palbociclib as a first line therapy. Additionally, it should be noted that FACT-B total scores worsened from baseline for both the palbociclib group, as combination relative to and placebo plus letrozole, effectively a monotherapy group in PALOMA-4 [61].

It could be speculated that while overall HRQoL was maintained, key components of quality of life may have improved while others worsened; however, when individual patient outcomes, such as pain, fatigue and physical functioning were analyzed, where reported, the results were similar such that there was an overall maintenance of quality of life. Results for pain across all RCTs, single-arm trials and RWE studies, instruments (QLQ-C30 Pain, BPI, FACT-B pain) and lines of therapy, were found to be maintained or improved from baseline among patients treated with palbociclib and were observed to be comparable or better in the palbociclib group compared with the placebo group in all RCTs. Fatigue and physical functioning findings were generally observed to be comparable between the palbociclib group and placebo group in RCTs and maintained from baseline across study types among patients treated with palbociclib, with some exceptions.

Generally maintained or improved results were also found for palbociclib across outcomes likely to be attributable to the treatment, as opposed to the disease, including sexual functioning, sexual enjoyment, upset by hair loss, systemic therapy side effects and TOI, with some exceptions. CFB across treatment-related outcomes were mostly found to be stable from baseline among patients treated with palbociclib, in first and all lines of therapy, however sexual enjoyment and systemic therapy side effects were reported to be worse from baseline in one study [36]. Although of note, sexual enjoyment and systemic therapy side effects were reported to be worse than baseline in both the palbociclib and placebo plus fulvestrant groups [36]. Across RCTs, the palbociclib group was generally found to be comparable or better than the control group for these treatment-related outcomes, with some exceptions observed for upset by hair loss and systemic therapy side effects. One study however, only measured ‘upset by hair loss’ in patients who experienced hair loss, resulting in a much lower sample size than other scales [36].

Overall, our study demonstrated that treatment with palbociclib generally maintains HRQoL in patients with HR+/HER2- aBC or mBC across RCTs, single-arm clinical trials and RWE studies. Findings from this review suggest that the addition of palbociclib to endocrine therapy for patients with HR+/HER2- aBC or mBC confers benefit on clinical outcomes, that does not come at the expense of a patient's HRQoL, both in a trial setting and the real-world. In fact, data suggest that HRQoL is largely preserved with the addition of palbociclib to endocrine therapy [11–13,72].

Other reviews have been conducted that focused on a broader population of breast cancer patients and/or a variety of treatments. A recent systematic review by Di Lauro et al. evaluating HRQoL results of breast cancer patients of any stage treated with a CDK4/6 inhibitor (including palbociclib), concluded that adding a CDK4/6 inhibitor to endocrine therapy generally did not worsen patients' HRQoL [21]. An additional review conducted by Zhou et al. in 2017 concluded that global health status was maintained or in some cases only slightly deteriorated from baseline in postmenopausal HR+/HER2- advanced breast cancer patients treated with endocrine therapy in combination with other treatments (such as palbociclib) in both first-line and endocrine-resistant settings; however, a variety of combination partners, in addition to palbociclib, were evaluated in this analysis [73]. While the overall findings presented herein are consistent with these earlier studies, this review provides a focused summary of palbociclib's impact on HRQoL in patients with HR+/HER2- aBC or mBC to better inform clinical decision-making in this patient population. However, it should be noted that HRQoL is just one factor among many (e.g., efficacy, patient preference, availability, cost) that should be considered in clinical decision making [4].

Consistent effects of palbociclib in maintaining HRQoL were also reported across studies in subgroups that are often underrepresented in clinical trials, including elderly, Asian and BIPOC patients [15,35,37,40,52,53,55]. There was a notable data gap in terms of results for elderly-specific HRQoL scales, which were not assessed in the included clinical trials and only reported in RWE studies. Additionally, HRQoL results were found to be comparable and relatively stable from baseline in patients with visceral metastases as well as among patients experiencing neutropenia, versus patients not having either. The presence of visceral metastases is considered an important disease characteristic and often acts as a stratification factor of patients within oncology clinical trials, while neutropenia is a common adverse event observed in patients treated with palbociclib [74,75]. Overall, our findings support that HRQoL is maintained with the use of palbociclib across multiple treatment lines, clinical characteristics and in high-risk populations.

Of significant note is the relative consistency in results between trial-based and real-world data. When palbociclib is evaluated in RWE studies, we continue to see preservation in HRQoL across a broader population of patients, including those who would have been excluded from clinical trials. Recent reviews have reported that although a number of real-world reports have been published since the approval of CDK 4/6 inhibitors plus ET, quality of life data is often rarely reported [76]. A systematic literature review by Harbeck et al. identified a total of 114 RWE studies on CDK 4/6 inhibitors in HR+/HER- advanced/metastatic breast cancer published between 2015 and 2019, of which only four reported PRO or HRQoL results [77]. All four studies evaluated patients treated with palbociclib, and no HRQoL data were reported for other CDK 4/6 inhibitors. Similarly, Di Lauro et al. in 2022 identified seven RWE reports in their SLR of HRQoL outcomes in breast cancer patient treated with any CDK4/6 inhibitor, with six evaluating patients treated with palbociclib and the remaining report focused on all CKD4/6/ inhibitors [21]. Thus, our review highlights the level of RWE evidence available for palbociclib, which may not be the same for other CDK 4/6 inhibitors.

While not the focus of the current review, the impact of other CDK 4/6 inhibitors, ribociclib and abemaciclib, on HRQoL, in patients with HR+/HER2- aBC or mBC has been evaluated in clinical trials. In MONARCH 2 [78] and MONARCH 3 [79], CFB results for the majority of EORTC QLQ-C30 and QLQ-BR23 functional and symptom scales were found to be generally comparable between the abemaciclib (abemaciclib + fulvestrant [MONARCH-2 [78]] or nonsteroidal aromatase inhibitor [MONARCH 3 [79]]) and control groups (placebo + fulvestrant [MONARCH-2 [78]] or nonsteroidal aromatase inhibitor [MONARCH 3 [79]]), with the exception of gastrointestinal items. The EORTC QLQ-C30 symptom subscale for diarrhea was found to significantly favor the control arm in both trials [78,79]. For ribociclib, a pooled analysis of QOL results from the MONALEESA-2, -3 and -7 trials, reported that ribociclib plus ET, generally delayed or maintained time to deterioration in QoL based on EORTC QLQ-C30 GHS, symptom and functional measures [80]. Overall, these CDK4/6 inhibitors demonstrated comparable impact on HRQoL to their control groups, similar to the findings from RCTs of palbociclib, as described herein. Furthermore, to our knowledge, while evidence on the impact of CDK4/6 inhibitors is growing, formal systematic literature reviews to summarize the totality of the HRQoL evidence for ribociclib or abemaciclib specifically in patients with HR+/HER2- aBC or mBC, have not yet been conducted.

A main source of heterogeneity across studies was the use of different HRQoL instruments. The presentation and calculation of results differed as well, with some studies reporting results for a single instrument such as CFB, TTD, or both. The variety of instruments to evaluate HRQoL and lack of consistent application across studies has been noted in previous systematic reviews [20,21]; and presents a significant challenge in comparing results between studies. Nevertheless, our review found that the literature consistently indicates that palbociclib is beneficial in terms of maintaining HRQoL in patients with HR+/HER2- aBC or mBC.

Our study also raises the importance of detailed reporting and consensus on the definition of minimal important difference (MID). Although some studies did not report using MIDs, the thresholds used across studies that did report MID definitions varied. While a within-patient or within-group change of at least 10 points from baseline was the most common definition [16,36,40,41,43,47,52,53,55], several studies used 2–10, 5–6 or 7–8 point thresholds [31,33,42,45,56]. For example, the FLIPPER trial defined deterioration of pain as measured by the QLQ-C30 scale as an increase in MID of 4 points [63], while the PALOMA-3 trial on the other hand defined deterioration of pain (QLQ-C30 scale) as an increase in MID of 10 points [36]. This aligns with a recent systematic review that found that the use of inconsistent definitions for MID was common in RCTs and RWE studies assessing HRQoL in patients with aBC [81]. Therefore,efore the utilization of different MID definitions may lead to differing interpretations of results and conclusions reported in various studies. Furthermore, this lack of standardization imposes a challenge and barrier to comparing the impact of palbociclib on HRQoL across studies. Establishing recommended MID value guidelines for individual PRO scales would be beneficial to help standardize definitions and facilitate the comparison of results across different studies.

Our review has several strengths. It was conducted and reported in accordance with the PRISMA statement, providing a comprehensive and rigorous assessment of the available research. Also, by focusing specifically on HR+/HER2- aBC or mBC patients treated with palbociclib, the present review also provides a more precise body of evidence as opposed to previous reviews that evaluated a broader patient population or CDK4/6 inhibitors as a whole [21,73]. To ensure all available evidence was captured, no date restrictions were applied to the literature searches. Conference abstracts were also included in an effort to integrate the latest research despite the often-limited information provided and reduced depth of possible analysis compared with full-text articles.

The limitations of this review should also be acknowledged. First, due to the level of heterogeneity in study designs, populations and treatment regimens, only qualitative findings are presented. The variability among studies makes quantitative analyses, such as meta-analyses, infeasible limiting the ability to draw definitive conclusions regarding palbociclib's impact on HRQoL within this review. Second, although RWE studies don't benefit from randomization, making internal validity and causality more difficult, RWE results can be informative in the appropriate context, as they often represent a wider patient population commonly excluded from clinical trials due to strict eligibility criteria. Similarly, many RWE studies use a single arm prospective longitudinal design, which may be challenging to put into context without a comparator group. However, these studies can offer valuable data, especially on PROs in a real-world population. For instance, change from baseline results can be particularly informative as they compare data for the same patients before and after treatment, and in the present review these RWE results were generally found to be consistent with those observed in the comparative clinical trials. Thirdly, as this study only focused on patients with HR+/HER2- aBC or mBC receiving palbociclib, the results may not be applicable for other populations, such as patients with early BC or patients receiving treatment with different CDK4/6 inhibitors. Additionally, the included HRQoL results are restricted to the time points at which they were assessed and may vary throughout treatment duration across studies. Side effects that persist after treatment which may impact QoL are not addressed in the scope of the current review. Exploring these potential side effects further is an important and interesting area of future research. Future studies may consider assessing these results quantitatively across common instruments in a meta-analysis or further investigate the relationship between HRQoL and clinical efficacy of palbociclib in patients with HR+/HER2- aBC or mBC, and other patient populations. Continued focused efforts should be made to incorporate PRO and HRQoL assessments more widely in treatment evaluations and clinical practice moving forward. Lastly, while the present review summarizes the available published HRQoL evidence on palbociclib, we recognize the importance of individual perspectives and patient experiences in relation to treatment decisions. The FDA highlighted the importance of patient perspectives for breast cancer treatment in 2015 as part of their patient voice work, which identified fatigue, pain and depression as symptoms having the greatest impact on patient lives, among other findings [9]. Additional studies should be conducted to better understand individual patient experiences following treatment with palbociclib.

The present review provides the first focused systematic assessment of HRQoL data in patients receiving palbociclib for treatment of HR+/HER2- aBC or mBC. Palbociclib was generally found to maintain patients' HRQoL across studies both in the clinical trial and real-world settings. Similar results were also shown for treatment-related outcomes and other important individual patient outcomes, such as pain, fatigue and physical functioning, as well as across different patient populations often underrepresented in clinical trials. Overall, current evidence suggests that HRQoL is largely preserved with the addition of palbociclib to endocrine therapy in patients with HR+/HER2- aBC or mBC.

All authors participated in the conception and design of the study. IA Samjoo, M Bartlett, A Hall and B-N Nguyen contributed to the literature review, data collection, analysis and interpretation of the data. J Doan, K Hanson, C Chen, JC Cappelleri, D Makari, LS Arruda, R Sandin, ML Smith, N Harbeck and M Karuturi contributed to the interpretation of the data and critically reviewed for importance of intellectual content for the work. All authors were responsible for drafting or reviewing the manuscript and for providing final approval. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work and have given their approval for this version to be published.

The authors thank Joanna Bielecki, employed by EVERSANA, Canada, who developed, conducted and documented the database searches.

This work was funded by Pfizer Inc. IA Samjoo, M Bartlett, A Hall and B-N Nguyen are employees of EVERSANA™, Canada, which was a paid consultant to Pfizer in connection with the development of this manuscript. J Doan, C Chen, JC Cappelleri, D Makari, LS Arruda and R Sandin are employees of Pfizer and own Pfizer stock. K Hanson serves as a consultant to Pfizer and receives compensation for these services. N Harbeck has received honoraria for lectures and/or consulting from AstraZeneca, Daiichi-Sankyo, Gilead, Lilly, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Seagen, Viatris and Zuelligpharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/