Background: Dysregulating mutations in PIK3CA, encoding the PI3K p110α subunit, occur in ̃40% of HR+/HER2– BCs. Inavolisib is a PI3Kα-specific inhibitor that also promotes degradation of mutant p110α. It has demonstrated encouraging preliminary antitumor activity in pts with PIK3CA-mutated HR+ BC as a monotherapy, and in combo with other anticancer agents. Methods: We included pts from NCT03006172 on treatment ≥1 year with inavolisib alone (Arm A), or in combo with palbo + letrozole (letro) (B), letro (C), fulvestrant (fulv) (D), or palbo + fulv (E; + metformin in Arm F for pts with body mass index ≥30 and/or HbA1c ≥5.7%). Inavolisib was administered orally daily (PO QD) at 3, 6, 9, or 12 mg (3+3 dose-escalation design); letro at 2.5 mg PO QD; palbo at 125 mg PO QD for 21/28 days; and fulv at 500 mg intramuscularly every 4 weeks, in 28-day cycles until intolerable toxicity/disease progression. Safety was assessed by NCI-CTCAE v4. Results: 57 female pts were included (cutoff 07/26/21; N = 1, 18, 6, 12, 15, 5 in Arms A–F); median age: 57 years (range 33–80); median lines of prior therapy: 2 (1–7). All but 2 pts, both in Arm B (3 mg), were assigned the 9 mg inavolisib recommended phase 3 dose. Overall median treatment duration: 19 months (range 12–45); median inavolisib cumulative dose intensity, 95%. The most frequent treatment-related adverse events (AEs; in ≥20 pts/35%) were hyperglycemia (68%), stomatitis (68%; grouped terms), neutropenia (58%), diarrhea (51%), nausea (39%), alopecia (35%), and rash (35%; grouped terms). The most frequent treatment-related Grade (G) 3–4 AEs (≥2 pts/4%) were neutropenia (47%), hyperglycemia (16%), leukopenia (9%), thrombocytopenia (9%), lymphopenia (7%), weight decreased, and hypokalemia (4% each). G3–4 neutropenia, leukopenia, thrombocytopenia, and lymphopenia were all reported in palbo arms. One G5 AE of pleural effusion was reported (disease progression-related). 39 pts (68%) had ≥1 AE resulting in study treatment modification (drug interruption/dose reduction/treatment withdrawal); 11 (19%) had an inavolisib dose reduction and 2 (4%) discontinued treatment due to an AE (1 related G2 diarrhea, 1 unrelated G3 cerebrovascular disorder). AEs typically occurred during the first 6 months and tended to be less frequent in later cycles. No new safety signals were observed with long-term inavolisib use. Conclusions: These data indicate acceptable long-term tolerability. The safety profile of pts on study treatment with inavolisib alone or in combo with endocrine-based anticancer therapies for ≥1 year was similar to that reported for the overall study population. Updated data will be presented. A phase 3 study of inavolisib + palbo + fulv is enrolling (NCT04191499; INAVO120). Clinical trial information: NCT03006172.