The certainty of evidence is downgraded by study limitations (unclear allocation concealment in half of the studies).
A Cochrane review «PARP (Poly ADP‐Ribose Polymerase) inhibitors for locally advanced or metastatic breast cancer»1 «Taylor AM, Chan DLH, Tio M et al. PARP (Poly ADP-Ribose Polymerase) inhibitors for locally advanced or metastatic breast cancer. Cochrane Database Syst Rev 2021;(4):CD011395. »1 included 5 studies with a total of 1474 subjects with breast cancer. There was a clear trend of small advantage in overall survival with poly ADP-ribose polymerase inhibitors (PARPi). In locally advanced/metastatic HER2-negative, BRCA germline mutated breast cancer, PARPi offer an improvement in progression-free survival (PFS), table «PARPi-containing regimen compared to non-PARPi regimen for locally advanced or metastatic breast cancer»1. There was no statistical heterogeneity for these outcomes. Subgroup analyses for PFS outcomes based on trial level data were performed for triple-negative breast cancer, hormone-positive and/or HER2-positive breast cancer, and BRCA1 and BRCA2 germline mutations.
| Outcome | Relative effect (95% CI) | Risk with control | Risk with intervention (PARPi) | No of subjects (studies) Quality of evidence |
|---|---|---|---|---|
| Overall Survival follow up: 24 months | HR 0.84 (0.76 to 1.00) | 550 per 1000 | 497 per 1000 (446 to 550) | 1435 (4) Moderate |
| Progression Free Survival follow up: 12 months | HR 0.63 (0.56 to 0.71) | 625 per 1000 | 461 per 1000 (423 to 502) | 1474 (5) High |
| Response Rate | RR 1.39 (1.24 to 1.54) | 489 per 1000 | 695 per 1000 (636 to 749) | 1185 (5) Low |
| Grade (severity al least 3) of adverse effects | RR 0.98 (0.91 to 1.04) | 645 per 1000 | 620 per 1000 (555 to 684) | 1443 (5) Moderate |
A double-blind, randomized phase III study «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 20»2 included 368 patients (abemaciclib + fulvestrant, n=182 placebo + fulvestrant, n=186). At the primary analysis (258 events), the hazard ratio (HR) was 0.73 (95% CI, 0.57 to 0.95; with median PFS 6.0 (95% CI, 5.6 to 8.6) versus 5.3 (95% CI, 3.7 to 5.6) months and 6-month PFS rates of 50% and 37% in the abemaciclib + fulvestrant and placebo + fulvestrant arms, respectively.
Another trial «Tao Z, Zhang J, Zheng Q, et al. Tibremciclib or Placebo Plus Fulvestrant in Hormone Receptor-Positive and ERBB2-Negative Advanced Breast Cancer After Endocrine Therapy: A Randomized Clinical Trial. JA»3 randomly assigned women with hormone receptor-positive and ERBB2-negative advanced breast cancer after endocrine therapy to receive tibremciclib plus fulvestrant (184 [67.2%]) or placebo plus fulvestrant (90 [32.8%]). 144 PFS events occurred (80 in the tibremciclib arm and 64 in the placebo arm), with a median follow-up of 12.9 months for both arms. Tibremciclib plus fulvestrant significantly improved PFS compared with placebo plus fulvestrant (median, 16.5 months vs 5.6 months; hazard ratio, 0.37; 95% CI, 0.27 to 0.52; P < .001). In patients with measurable disease, tibremciclib plus fulvestrant achieved an objective response rate of 45.6% (95% CI, 37.6% to 53.7%) compared with 12.9% (95% CI, 6.1% to 23.0%) in the placebo arm. The most common grade 3 or higher treatment-emergent adverse events in the tibremciclib vs placebo arm were neutropenia (15.2% vs 5.6%, respectively), anemia (12.0% vs 4.4%, respectively), and hypokalemia (12.0% vs 0%, respectively).