Background: Oral anticancer drug annual out-of-pocket costs (OOPCs) for Medicare beneficiaries are frequently > $10,000. Many of these medications are available as multiple formulations (e.g., tablet/capsule) and multiple strengths (e.g., 25mg/50mg). Oral medications are typically priced per unit (pill), allowing for more cost-effective prescribing when patients use fewer pills to obtain a recommended dose. It is unclear whether cancer drugs follow this traditional paradigm. We sought to assess the relationship between drug formulation features and OOPCs. Methods: We included 20 oral anticancer drugs with the highest spending in Medicare Part D in 2020. For each drug, we identified formulations, strengths, and schedules using NCCN guidelines and UptoDate. For each product, we calculated a lowest expected annual drug OOPC for all relevant strengths/schedules using the 2022 Part D Plan Finder. For example, the drug osimertinib is available in 40 and 80 mg tablets, with total daily doses of 80 and 160mg, reflecting 4 pricing scenarios. We assessed costs for 1 year of monthly fills. We compared cost ratios across formulations for each drug. Results: Of the 20 drugs, 17 (85%) were available as brand-name only; 3 (15%) were also available as generic. Fifteen (75%) were available as a single formulation only (e.g., tablet only); 5 (25%) were available as multiple formulations (e.g., tablet and capsule). Eighteen (90%) were available in multiple strengths. Median annual drug OOPCs was $12,979. For brand vs generic comparisons (n = 4, keeping other variables constant, 1 drug could have > 1 comparison due to different strengths), brand coverage for imatinib and 250 mg abiraterone tablets was limited, leading to high cost ratios (brand/generic > 50). For 2 other comparisons, the brand was less costly (abiraterone 500 mg tablets, ratio 0.85) and more costly (everolimus 10 mg tablets, ratio 1.18) for 1 each. For tablet vs capsules/others (n = 4), tablets were cheaper for 2 (ratio, 0.63- 0.96), a little more costly for 1 (ratio 1.04), and a lot more costly for 1 (ratio 2.13, ibrutinib 140 mg). For comparisons across strengths of the same formulation to achieve the same total dose (n = 14), using lower strength/higher fill quantity was more costly for 10 drugs (median ratio 1.79), the same for 1, and less costly for 3 (ratios 0.35- 0.89). Conclusions: Even when considering the least costly Part D plan, 2022 oral anticancer drug OOPCs remain high. Counter to expectations, in some cases generics were more costly than brands, and more pills at a lower dose were less costly than fewer pills. There was no consistent pattern. Oncologists and pharmacists cannot be expected to know the unpredictable OOPC ramifications of biologically equivalent prescription decisions. As cancer primarily affects older adults, often living on fixed incomes, policy-level change to lower OOPCs are necessary to avoid financial ruin and enhance access for Medicare beneficiaries.