Is rechallenge with CDK4/6 inhibitors beyond progression reasonable for patients with hormone receptor-positive and HER2-negative advanced breast cancer?—a commentary on the PALMIRA trial
Editorial Commentary

Is rechallenge with CDK4/6 inhibitors beyond progression reasonable for patients with hormone receptor-positive and HER2-negative advanced breast cancer?—a commentary on the PALMIRA trial

Mai Shimura ORCID logo, Toru Mukohara ORCID logo

Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan

Correspondence to: Toru Mukohara, MD, DMedSc. Department of Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa 277-8577, Japan. Email: tmukohar@east.ncc.go.jp.

Comment on: Llombart-Cussac A, Harper-Wynne C, Perelló A, et al. Second-line endocrine therapy with or without palbociclib rechallenge in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: PALMIRA Trial. J Clin Oncol 2025;43:2084-93.

Keywords: Hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2− ABC); cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i); palbociclib; beyond progression; rechallenge

Submitted Oct 22, 2025. Accepted for publication Jan 28, 2026. Published online Apr 24, 2026.

doi: 10.21037/cco-2025-aw-139

For more than a decade, aromatase inhibitors (AIs) have been the standard first-line endocrine therapy (ET) for patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). However, the emergence of the cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is), palbociclib, abemaciclib, and ribociclib, has changed the treatment landscape. The PALOMA-2 (1), MONARCH-3 (2), and MONALEESA-2 (3) trials consistently demonstrated that combination therapy of CDK4/6is with an AI significantly prolonged the progression-free survival (PFS) of postmenopausal patients compared with AI monotherapy. Similarly, for premenopausal patients, the MONALEESA-7 trial demonstrated that adding ribociclib to AIs or tamoxifen plus goserelin prolonged PFS and overall survival (OS) compared with ET alone (4). The use of fulvestrant plus CDK4/6i, commonly used for patients who have recurrence of breast cancer during or within 12 months after adjuvant AI monotherapy, is based on findings from the PALOMA-3 (palbociclib) (5), MONARCH-2 (abemaciclib) (6), and MONALEESA-3 (ribociclib) (7) trials, which demonstrated the superiority of fulvestrant combined with CDK4/6i over fulvestrant alone for this patient population. Collectively, the combination of ET and CDK4/6is is the current standard first-line treatment for patients with HR+/HER2− ABC (8-11).

When progression on first-line treatment occurs, choosing subsequent treatments based on genetic alterations is becoming the mainstream approach. In HR+/HER2− breast cancer, gene alterations of signaling molecules of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin pathway (hereinafter referred to as the PI3K pathway), which lead to the aberrant activation of the pathway, are frequently observed. In particular, mutations in PIK3CA, encoding the α isoform of the catalytic subunit of PI3K, are observed in approximately 40% of breast cancer cases (12). Drugs targeting the enhanced PI3K pathway include capivasertib (AKT inhibitor), inavolisib (PI3K inhibitor), and alpelisib (PI3K inhibitor). In the CAPItello-291 trial (13), capivasertib plus fulvestrant was compared with placebo plus fulvestrant in patients with disease progression on AI with or without CDK4/6is. Of these patients, 69.1% had previously received a CDK4/6i. As a result, capivasertib plus fulvestrant extended PFS in the overall population and in a subgroup with PI3K pathway (PIK3CA, AKT1, or PTEN) alterations. The United States Food and Drug Administration (FDA) approved capivasertib plus fulvestrant combination therapy for patients with HR+HER2− ABC with PI3K pathway alterations who experienced disease progression on ETs. Although the SOLAR-1 trial also demonstrated the superiority of alpelisib plus fulvestrant to placebo plus fulvestrant for PFS, few patients in this trial (6%) had a history of receiving CDK4/6is (14). Therefore, given that CDK4/6is plus ET is now the standard first-line treatment, these findings may be less applicable to the current setting than capivasertib.

Mutations in the ESR1 gene, encoding estrogen receptor (ER) α, which promotes resistance to AIs, are commonly observed after treatment with an AI plus CDK4/6is. Oral selective ER degraders (SERDs) such as elacestrant, imlunestrant, and camizestrant, as well as vepdegestrant, a proteolysis-targeting chimera ER degrader, have been introduced for ESR1 mutation-positive cases. In the EMERALD trial, which enrolled patients with HR+/HER2− ABC who had received one or two lines of ET, elacestrant significantly prolonged PFS compared with standard ET, AI, or fulvestrant, in the overall population (15). Because a marked PFS improvement was observed in the ESR1 mutation-positive subgroup, the FDA approved elacestrant for ESR1-mutant disease only. Consequently, guidelines recommend elacestrant for patients with detectable ESR1 mutations who experience disease progression on ET (10,11). Moreover, the randomized phase III EMBER-3 trial, in which 59.8% of participants previously received CDK4/6is, demonstrated that treatment with imlunestrant led to significantly longer PFS than standard therapy with exemestane or fulvestrant, among those with ESR1 mutations (16). The FDA recently approved imlunestrant for HR+/HER2− and ESR1-mutated advanced or metastatic breast cancer. Similarly, in ESR1-mutated patients with a treatment history of CDK4/6is and ET, vepdegestrant prolonged PFS compared with fulvestrant (17). Furthermore, in a randomized trial of patients who developed an ESR1 mutation during AI plus CDK4/6i therapy, switching to CDK4/6i plus camizestrant improved PFS compared with continuing the AI plus CDK4/6i (18). Although vepdegestrant and camizestrant are pending FDA approval as of 14 October, 2025, these agents may soon be used in clinical practice.

For cases without ESR1 or PI3K pathway mutations, treatment options include fulvestrant monotherapy, exemestane plus everolimus, or fulvestrant plus everolimus. However, the efficacy of everolimus plus exemestane combination therapy as second-line or later treatment after non-steroidal AI therapy was demonstrated in an era before CDK4/6is were available (BOLERO-2 trial) (19). In addition, the PrE0102 trial, which demonstrated the superiority of everolimus plus fulvestrant over placebo plus fulvestrant, was a relatively small randomized phase II study (n=131), including only two patients who received prior CDK4/6is (20). Therefore, no definitive standard therapy exists for patients who progress with AI plus CDK4/6i without ESR1 or PI3K pathway alterations. Multiple trials have tested the value of rechallenging CDK4/6is on subsequent ET following progression with ET plus a CDK4/6i. The results of these trials are particularly important from the perspective of the treatment of patients without ESR1 mutations and PI3K pathway alterations.

Recently, the results of one such investigation, the PALMIRA trial, were published (21). The PALMIRA trial is an international randomized phase II study investigating the efficacy of rechallenging palbociclib with an alternative ET as a second-line treatment for patients with HR+/HER2− ABC who progressed after receiving palbociclib plus ET as first-line therapy. A total of 198 patients were randomized at a 2:1 ratio to the palbociclib plus ET group (n=136) or the ET alone group (n=62). PFS, the primary endpoint, was not significantly different between the groups [the median PFS in the palbociclib rechallenge group vs. ET alone group, 4.9 vs. 3.6 months; hazard ratio, 0.84; 95% confidence interval (CI): 0.66–1.07; P=0.149] (Table 1). A comparison of the efficacy between the groups by ESR1 or PIK3CA mutation status was not provided. Treatment emergent adverse events were more frequent in the palbociclib group (grade ≥3, 47.4% vs. 10.0%) (21).

Table 1

Summary of trials that tested rechallenging CDK4/6i beyond progression

Study ID Study design Menopausal status Previous regimen Previous CDK4/6i Intervention arm Control arm Primary endpoint PFS (months)† HR for PFS by duration of previous CDK4/6i (interaction P value) HR for PFS by presence or absence of ESR1 mutations (interaction P value) HR for PFS by presence or absence of PI3K pathway mutations‡ (interaction P value) OS (months)† ORR (intervention vs. control) CBR (intervention vs. control)
Llombart-Cussac 2025 (PALMIRA) Phase II RCT Pre-, 12.1%; post-, 87.9% PAL + ET PAL, 100% PAL + 2nd-line ET (AI or FUL) 2nd-line ET alone (AI or FUL) PFS 4.9 vs. 3.6; 0.84 (0.66–1.07) 6 to <12 months, 0.93; ≥12 months, 0.83 (0.734) N/A N/A 28.3 vs. 28.8; 1.06 (0.75–1.51) 4.4% vs. 1.6% 41.9% vs. 27.4%
Mayer 2024 (PACE) Phase II RCT Pre-, 18.2%; post-, 80.9%§ CDK4/6i + AI PAL, 90.9%; RIB, 4.5%; ABM, 4.1% PAL + FUL FUL PFS 4.6 vs. 4.8; 1.11 (0.79–1.55) N/A Present, 0.68; absent, 1.70 (N/A) Present, 0.56; absent, 1.44 (N/A) 24.6 vs. 27.5; 1.02 (0.67–1.56) 9.0% vs. 7.3% 32.4% vs. 29.1%
Kalinsky 2023 (MAINTAIN) Phase II RCT N/A CDK4/6i + AI PAL, 86.5%; RIB, 11.8%; ABM, 1.7% RIB + ET (FUL or EXE) Placebo + ET (FUL or EXE) PFS 5.3 vs. 2.8; 0.57 (0.39–0.85) ≤12 months, 0.36; >12 months, 0.76 (0.035) Present, 0.88; absent, 0.33 with ET (0.455). Present, 1.22; absent, 0.30 with FUL (N/A) Present, 1.02; absent, 0.39 with FUL (N/A) N/A 20% vs. 11% 43% vs. 25%
Kalinsky 2024 (postMONARCH) Phase III RCT N/A CDK4/6i + AI PAL, 59%; RIB, 33.2%; ABM, 7.6% ABM + FUL Placebo + FUL PFS 6.0 vs. 5.3; 0.73 (0.57–0.95) <12 months for ABC or after adjuvant CDK4/6i, 0.80; ≥12 months, 0.70 (0.633) Present, 0.79; absent, 0.78 (0.977) Present, 0.86; absent, 0.73 (0.553) N/A 17% vs. 7% N/A

†, in the PACE trial, data are presented as HR (90% CI), whereas those in the other trials are presented as HR (95% CI). ‡, ctDNA-detected PIK3CA mutations for the PACE and MAINTAIN trials and ctDNA-detected PIK3CA/AKT1/PTEN alterations for the postMONARCH trial. §, in the PACE trial, percentages for menopausal status do not sum to 100% because of missing data. ABC, advanced breast cancer; ABM, abemaciclib; AI, aromatase inhibitor; CBR, clinical benefit rate; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; CI, confidence interval; ET, endocrine therapy; EXE, exemestane; FUL, fulvestrant; HR, hazard ratio; N/A, not available; ORR, overall response rate; OS, overall survival; PAL, palbociclib; PFS, progression-free survival; PI3K, phosphoinositide 3-kinase; RCT, randomized controlled trial; RIB, ribociclib.

The PACE trial was a randomized phase II study of patients with HR+/HER2− ABC who progressed on prior therapy with a CDK4/6i and an AI. A total of 220 patients were randomized at a 1:2:1 ratio to fulvestrant, fulvestrant plus palbociclib, or fulvestrant plus palbociclib and avelumab (22). Because approximately 90% of patients received palbociclib as a prior CDK4/6i, this trial should be considered a “palbociclib to palbociclib trial”, similar to the PALMIRA trial. The results showed that fulvestrant plus palbociclib did not improve PFS compared with fulvestrant monotherapy (median PFS, 4.6 vs. 4.8 months; hazard ratio, 1.11; 90% CI: 0.79–1.55; P=0.62), consistent with the PALMIRA trial (Table 1). Based on an exploratory analysis of baseline genetic mutations in ESR1 and PIK3CA, patients positive for mutations appeared to derive greater benefit from adding palbociclib to fulvestrant (Table 1) (22).

Conversely, the randomized, double-blind phase II MAINTAIN trial compared ribociclib plus a switched ET (fulvestrant or exemestane) with placebo plus the ET in 119 patients whose disease had progressed on previous CDK4/6is (23). The ET plus ribociclib group demonstrated a statistically significant improvement in PFS compared with the control group (median PFS, 5.29 vs. 2.76 months; hazard ratio, 0.57; 95% CI: 0.39–0.85; P=0.006) (Table 1). Subgroup analyses suggested similar benefits regardless of prior CDK4/6i treatment, although most patients had received palbociclib as a prior therapy (palbociclib, 86.5%; ribociclib, 11.8%; and abemaciclib, 1.7%). In contrast with the result of the PACE trial, an exploratory analysis showed that ribociclib plus fulvestrant significantly improved PFS vs. placebo plus fulvestrant in patients without ESR1 mutations (hazard ratio, 0.30; 95% CI: 0.15–0.62), but not in patients with ESR1 mutations (hazard ratio, 1.22; 95% CI: 0.59–2.49). Similarly, an exploratory analysis with a small cohort demonstrated an improvement in PFS by adding ribociclib to fulvestrant only in the PIK3CA wild-type population (hazard ratio, 0.39; 95% CI: 0.22–0.71), but not in the PIK3CA-mutant population (hazard ratio, 1.02; 95% CI: 0.39–2.68) (23).

The phase III postMONARCH trial compared fulvestrant plus abemaciclib (n=182) with fulvestrant plus placebo (n=186) after disease progression with a CDK4/6i plus AI. Compared with the placebo group, the abemaciclib combination therapy group significantly prolonged PFS (median PFS, 6.0 vs. 5.3 months; hazard ratio, 0.73; 95% CI: 0.57–0.95; nominal P=0.017) (Table 1) (24). In this trial, 59% of patients received prior treatment with palbociclib, and the benefit appeared to be limited to them based on a subgroup analysis. The effect of adding abemaciclib was consistent across the biomarker subgroups, including ESR1 and PI3K pathway mutations (Table 1) (24).

In 2025, a meta-analysis investigating continuing CDK 4/6is beyond progression in HR+/HER2− ABC was published (25). This meta-analysis integrated 13 studies, including the four randomized controlled studies introduced above, two single-arm prospective studies, and seven retrospective studies, with a total of 1,530 patients, 96.3% of whom received palbociclib as first-line therapy. In eight trials, switching to another CDK4/6i was the intervention. In four trials, the same CDK4/6i was continued with a change in ET, and one trial tested both a switch and the same CDK4/6i in two distinct cohorts. The median PFS was 5.3 months both in the CDK4/6i continuation group and the control group. The objective response rate was 14% in the CDK4/6is continuation group and 6% in the control group. Although integrated data of four randomized controlled trials showed a statistically significant improvement of PFS in the CDK4/6is continuation groups compared with control groups (hazard ratio, 0.77; 95% CI: 0.62–0.96), the improvement appeared to be derived from two trials (MAINTAIN and postMONARCH) in which CDK4/6i was switched to non-palbociclib (25).

Collectively, the continuation of CDK4/6is beyond progression did not show efficacy for palbociclib (21,22), whereas improved PFS was observed with ribociclib (23) and abemaciclib (24) (Table 1). It is difficult to identify the patient population that would benefit from continued CDK4/6 inhibition. Patients with visceral crisis were excluded from all four randomized trials listed in Table 1, while the use of ET plus CDK4/6i for visceral crisis has been suggested in the first-line ET setting (26). Therefore, patients with visceral crisis should not be considered candidates for continuing CDK4/6i treatment beyond progression. In the MAINTAIN trial, patients who had received a shorter duration of previous CDK4/6i treatment benefited more from continued treatment. However, this trend was not observed in the other trials (Table 1). It is also unclear whether ESR1 mutations and PI3K pathway alterations are related to the efficacy of continuing CDK4/6is because of inconsistent results between the trials (Table 1). These biomarker subgroup analyses are exploratory and underpowered. However, ESR1-mutated disease now is the area covered by oral SERDs, which has made CDK4/6is rechallenge less relevant in this subgroup. It is difficult to determine a definitive reason for why there is a discrepancy in the results between “(primarily) palbociclib to palbociclib” and “(primarily) palbociclib to ribociclib or abemaciclib” trials. However, a couple of possibilities can be considered. First, palbociclib may be somewhat a weaker inhibitor compared with the other two inhibitors. Previous studies showed that palbociclib has a similar potency to CDK4 and CDK6, whereas abemaciclib and ribociclib have greater potency against CDK4 than CDK6. In addition, abemaciclib inhibits multiple kinases other than CDK4 and CDK6 (27). In randomized controlled trials of CDK4/6is in a second-line ET setting for ABC, ribociclib (7) and abemaciclib (28) demonstrated superior OS compared with the control group, whereas palbociclib did not, at least when examined in a protocol-specified OS analysis (29). Additionally, efficacy was demonstrated for abemaciclib (30) and ribociclib (31), but not palbociclib, in adjuvant settings when added to ET (32). Second, switching to another CDK4/6i itself may be important to demonstrate benefit. To clarify which hypothesis is true, data of “ribociclib to ribociclib”, “abemaciclib to abemaciclib”, and “ribociclib or abemaciclib to another CDK4/6i” trials are required. Although some studies have addressed this clinical question (33), it is unlikely that large randomized trials will be conducted to test every hypothesis. However, real-world evidence may be helpful.

In conclusion, the PALMIRA trial did not demonstrate efficacy for rechallenge with palbociclib in patients previously treated with palbociclib. However, the efficacy of other CDK4/6is is emerging in patients beyond progression. Therefore, based on expert opinion, abemaciclib or ribociclib may be considered as a second-line ET for selected patients, particularly for those who received palbociclib as a first-line ET and have no ESR1 mutations or PIK3CA/AKT1/PTEN alterations. Further studies, particularly those using real-world data, are warranted to clarify the optimal approach for rechallenging CDK4/6is.

Acknowledgments

We thank J. Ludovic Croxford, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this article.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2025-aw-139/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2025-aw-139/coif). T.M. received research grants from Sysmex, Sanofi, MSD, Pfizer, Novartis, Chugai, AstraZeneca, Ono, Daiichi-Sankyo, and Gilead Sciences; lecture fees from Eisai, Pfizer, Novartis, Chugai, Eli Lilly, AstraZeneca, Kyowa-Kirin, Taiho, and Daiichi-Sankyo; and served on an advisory board for AstraZeneca and Pfizer. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

  1. Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 2016;375:1925-36. [Crossref] [PubMed]
  2. Goetz MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol 2017;35:3638-46. [Crossref] [PubMed]
  3. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med 2016;375:1738-48. [Crossref] [PubMed]
  4. Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol 2018;19:904-15. [Crossref] [PubMed]
  5. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016;17:425-39. [Crossref] [PubMed]
  6. Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol 2017;35:2875-84. [Crossref] [PubMed]
  7. Slamon DJ, Neven P, Chia SKL, et al. Updated overall survival (OS) results from the phase III MONALEESA-3 trial of postmenopausal patients (pts) with HR+/HER2-advanced breast cancer (ABC) treated with fulvestrant (FUL)±ribociclib (RIB). J Clin Oncol 2021;39:1001. [Crossref]
  8. Jerzak KJ, Bouganim N, Brezden-Masley C, et al. HR+/HER2- Advanced Breast Cancer Treatment in the First-Line Setting: Expert Review. Curr Oncol 2023;30:5425-47. [Crossref] [PubMed]
  9. Cardoso F, Paluch-Shimon S, Schumacher-Wulf E, et al. 6th and 7th International consensus guidelines for the management of advanced breast cancer (ABC guidelines 6 and 7). Breast 2024;76:103756. [Crossref] [PubMed]
  10. Masuda J, Sakai H, Tsurutani J, et al. Efficacy, safety, and biomarker analysis of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR-positive HER2-negative metastatic breast cancer: a phase II study (WJOG11418B NEWFLAME trial). J Immunother Cancer 2023;11:e007126. [Crossref] [PubMed]
  11. Trapani D, Martins-Branco D, Curigliano G, et al. Updated treatment recommendations for systemic treatment: from the ESMO Metastatic Breast Cancer Living Guideline. Ann Oncol 2025;36:1414-8. [Crossref] [PubMed]
  12. Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61-70. [Crossref] [PubMed]
  13. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med 2023;388:2058-70. [Crossref] [PubMed]
  14. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med 2019;380:1929-40. [Crossref] [PubMed]
  15. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. J Clin Oncol 2022;40:3246-56. [Crossref] [PubMed]
  16. Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant with or without Abemaciclib in Advanced Breast Cancer. N Engl J Med 2025;392:1189-202. [Crossref] [PubMed]
  17. Campone M, De Laurentiis M, Jhaveri K, et al. Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer. N Engl J Med 2025;393:556-68. [Crossref] [PubMed]
  18. Bidard FC, Mayer EL, Park YH, et al. First-Line Camizestrant for Emerging ESR1-Mutated Advanced Breast Cancer. N Engl J Med 2025;393:569-80. [Crossref] [PubMed]
  19. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520-9. [Crossref] [PubMed]
  20. Kornblum N, Zhao F, Manola J, et al. Randomized Phase II Trial of Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy: Results of PrE0102. J Clin Oncol 2018;36:1556-63. [Crossref] [PubMed]
  21. Llombart-Cussac A, Harper-Wynne C, Perelló A, et al. Second-line endocrine therapy with or without palbociclib rechallenge in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: PALMIRA Trial. J Clin Oncol 2025;43:2084-93. [Crossref] [PubMed]
  22. Mayer EL, Ren Y, Wagle N, et al. PACE: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab After Progression on Cyclin-Dependent Kinase 4/6 Inhibitor and Aromatase Inhibitor for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor-Negative Metastatic Breast Cancer. J Clin Oncol 2024;42:2050-60. [Crossref] [PubMed]
  23. Kalinsky K, Accordino MK, Chiuzan C, et al. Randomized Phase II Trial of Endocrine Therapy With or Without Ribociclib After Progression on Cyclin-Dependent Kinase 4/6 Inhibition in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: MAINTAIN Trial. J Clin Oncol 2023;41:4004-13. [Crossref] [PubMed]
  24. Kalinsky K, Bianchini G, Hamilton E, et al. Abemaciclib Plus Fulvestrant in Advanced Breast Cancer After Progression on CDK4/6 Inhibition: Results From the Phase III postMONARCH Trial. J Clin Oncol 2025;43:1101-12. [Crossref] [PubMed]
  25. Pathak N, Kumar S, Gimenez DM, et al. Continuing Cyclin-Dependent Kinase 4/6 Inhibitors Beyond Progression in Advanced Breast Cancer: A Meta-Analysis. Cancers (Basel) 2025;17:1609. [Crossref] [PubMed]
  26. Pangarsa EA, Astuti PD, Rizky D, et al. First-line endocrine therapy combined with CDK 4/6 inhibitor in disseminated carcinomatosis of bone marrow (DCBM) luminal breast cancer: a case report. J Med Case Rep 2024;18:591. [Crossref] [PubMed]
  27. George MA, Qureshi S, Omene C, et al. Clinical and Pharmacologic Differences of CDK4/6 Inhibitors in Breast Cancer. Front Oncol 2021;11:693104. [Crossref] [PubMed]
  28. Sledge GW Jr, Toi M, Neven P, et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol 2020;6:116-24. [Crossref] [PubMed]
  29. Turner NC, Slamon DJ, Ro J, et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med 2018;379:1926-36. [Crossref] [PubMed]
  30. Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol 2020;38:3987-98. [Crossref] [PubMed]
  31. Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med 2024;390:1080-91. [Crossref] [PubMed]
  32. Gnant M, Dueck AC, Frantal S, et al. Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol 2022;40:282-93. [Crossref] [PubMed]
  33. Nishimura M, Kogawa T, Akaishi Y, et al. Abstract OT2-19-02: Clinical evaluation of the efficacy and liquid molecular analysis of abemaciclib rechallenge upon progression to abemaciclib combination therapies for ER-positive HER2-negative metastatic breast cancer patients. Cancer Res 2022;82:OT2-19-02.
Cite this article as: Shimura M, Mukohara T. Is rechallenge with CDK4/6 inhibitors beyond progression reasonable for patients with hormone receptor-positive and HER2-negative advanced breast cancer?—a commentary on the PALMIRA trial. Chin Clin Oncol 2026;15(2):27. doi: 10.21037/cco-2025-aw-139

Article Options

Download Citation

Share