Capivasertib and fulvestrant for patients with hormone receptor-positive, HER2-negative advanced breast cancer (CAPItello-291): patient-reported outcomes from a phase 3, randomised, double-blind, placebo-controlled trial

Messaggi chiave

• CAPItello-291 è uno studio di fase III ancora in corso su fulvestrant ± capivasertib, un inibitore tirosin-chinasico di AKT, in pazienti affetti da carcinoma mammario avanzato HR+/HER2- con recidiva o progressione della malattia durante o dopo trattamento con un inibitore delle aromatasi. In questa sede, si riportano i risultati relativi agli esiti riferiti dai pazienti in termini di qualità della vita (QOL) correlata alla salute, funzionamento, sintomi e tollerabilità della terapia.
• Nel periodo giugno 2020 – ottobre 2021, è stato arruolato e randomizzato un totale di 708 pazienti. I punteggi relativi a stato di salute globale/QOL misurati con questionario EORTC QLQ-C30 non hanno mostrato variazioni significative rispetto al basale e sono stati simili nel braccio sperimentale e nei controlli lungo tutto il periodo dello studio. Il tempo mediano al deterioramento è risultato pari a 24,9 vs 12,0 mesi (hazard ratio [HR], 0,70; IC 95%, 0,53-0,92). Considerando tutte le sottoscale di EORTC QLQ-C30 e QLQ-BR23, solo la diarrea è stata peggiore con capivasertib (HR di tempo al deterioramento, 2,75; IC 95%, 2,01-3,81).
• Nella valutazione dei sintomi con questionario PRO-CTCAE, la percentuale di pazienti che segnalava feci molli e acquose “frequentemente” o “quasi costantemente” è stata del 29% superiore nel gruppo capivasertib-fulvestrant al Ciclo 1, Giorno 15, riducendosi nei cicli successivi. Altri sintomi secondo PRO-CTCAE-sono risultati lievi o del tutto assenti nella maggior parte dei pazienti di entrambi i gruppi, per tutta la durata del trattamento. Perlopiù, i pazienti hanno riferito di essere disturbati “poco” o “per nulla” dagli effetti collaterali, a prescindere dal trattamento ricevuto.

Abstract

Background

• CAPItello-291 is an ongoing phase 3 trial in which capivasertib-fulvestrant significantly improved progression-free survival versus placebo-fulvestrant in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had relapse or disease progression during or after aromatase inhibitor treatment, in both the overall population and in patients with PIK3CA, AKT1, or PTEN-altered tumours.
• This study further explored patient-reported health-related quality of life (HRQOL), functioning, symptoms, and symptom tolerability in CAPItello-291.

Methods

• This phase 3, randomised, double-blind, placebo-controlled trial, which was conducted across 193 hospitals and cancer centres in 19 countries, enrolled women with any menopausal status or men, aged ≥18 years (≥20 years in Japan), with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who had relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase (CDK) 4 or 6 inhibitor therapy.
• Patients had an Eastern Cooperative Oncology Group/WHO performance score of 0 or 1 and could have received up to two previous lines of endocrine therapy and up to one previous line of chemotherapy for advanced disease.
• Patients were randomly assigned (1:1) using block randomisation (stratified according to the presence or absence of liver metastases, previous use of a CDK4/6 inhibitor [yes vs no], and geographical region) to receive oral capivasertib 400 mg (twice daily for 4 days, followed by 3 days off) plus intramuscular fulvestrant 500 mg (every 14 days for the first three injections, then every 28 days) or placebo with matching fulvestrant dosing.
• The dual primary endpoint of the trial was investigator-assessed progression-free survival assessed both in the overall population and among patients with PIK3CA, AKT1, or PTEN-altered tumours.
• The EORTC Quality of Life Questionnaire 30-item core module (QLQ-C30) and breast module (QLQ-BR23), Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and Patient Global Impression of Treatment Tolerability (PGI-TT) questionnaires were used to assess patient-reported outcomes.
• Evaluation of EORTC QLQ-C30 and EORTC QLQ-BR23 were secondary endpoints and evaluation of PRO-CTCAE and PGI-TT were pre-defined exploratory endpoints, and these endpoints are the subject of analysis in this Article.
• Data were collected at baseline and prespecified timepoints.
• Patient-reported outcomes were analysed in all randomly assigned patients with an evaluable baseline assessment and at least one evaluable post-baseline assessment.
• Change from baseline was assessed using mixed model with repeated measures for EORTC QLQ-C30 and summarised for QLQ-BR23.
• Time to deterioration was described using the Kaplan-Meier method.
• PGI-TT and PRO-CTCAE responses were summarised at each treatment cycle.
• Patient-reported outcomes were not prospectively powered for statistical comparison.
• The trial is registered with ClinicalTrials.gov, NCT04305496.

Findings

• Between June 2, 2020, and Oct 13, 2021, 901 patients were enrolled, of whom 708 patients were randomly assigned to receive capivasertib-fulvestrant (n = 355) or placebo-fulvestrant (n = 353).
• The median age of the patients was 59 years (IQR 51-67) in the capivasertib-fulvestrant group and 58 years (IQR 49-66) in the placebo-fulvestrant group.
• At data cutoff (Aug 15, 2022), the median duration of follow-up for progression-free survival in censored patients was 13.0 months (IQR 9.1-16.7) for capivasertib-fulvestrant and 12.7 months (IQR 2.0-16.4) for placebo-fulvestrant in the overall population.
• EORTC QLQ-C30 global health status/quality of life (GHS/QOL) scores were maintained from baseline and were similar between treatment groups throughout the study period (difference in mean change from baseline of -2.5 [95% CI -4.5 to -0.6] with capivasertib-fulvestrant vs -5.6 [-7.9 to -3.4] with placebo-fulvestrant; treatment difference 3.1 [95% CI 0.2 to 6.0]).
• Median time to deterioration in EORTC QLQ-C30 GHS/QOL was 24.9 months (95% CI 13.8 to not reached) in the capivasertib-fulvestrant group and 12.0 months (10.2 to 15.7) in the placebo-fulvestrant group (hazard ratio [HR] 0.70, 95% CI 0.53 to 0.92).
• Time to deterioration HRs for all EORTC QLQ-C30 and QLQ-BR23 subscale scores showed little difference between the treatment groups, except for diarrhoea, which was worse in the capivasertib-fulvestrant group than in the placebo-fulvestrant group (HR 2.75, 95% CI 2.01-3.81).
• In PRO-CTCAE symptom assessment, the proportion of patients reporting loose and watery stools “frequently” or “almost constantly” was 29% higher at cycle 1, day 15 in the capivasertib-fulvestrant group than in the placebo-fulvestrant group, decreasing at subsequent cycles.
• Other PRO-CTCAE-reported symptoms (rash, mouth or throat sores, itchy skin, and numbness or tingling in hands or feet) were absent or mild in most patients in both groups throughout treatment.
• According to the PGI-TT, most patients in both groups reported “not at all” or “a little bit” of bother from treatment side-effects.

Interpretation

• Patient-reported outcomes from CAPItello-291 demonstrated that capivasertib-fulvestrant delayed time to deterioration of GHS/QOL and maintained other dimensions of HRQOL (except symptoms of diarrhoea) similarly to fulvestrant.
• With the clinical efficacy and manageable safety profile, these exploratory results further support the positive benefit-risk profile of capivasertib-fulvestrant in this population.