A Prospective Trial of Serum Folate Levels in Women with Solid Tumor Malignancies Treated with Olaparib
Authors: Owczarzak Laura , Yun Nicole , Winkelman Lois Anaya , Shammo Jamile , Usha Lydia 
Published: December 2024

Background:
Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor that was initially approved by the Food and Drug Administration (FDA) to treat advanced ovarian cancers in women with germline BRCA mutations (Yao, 2014). Olaparib functions by inhibiting PARP enzymes, which repair DNA breaks and regulate the cell cycle (LynparzaTM, AstraZeneca Pharmaceuticals LP; 2023), (Yohannan et al, 2019). The most common adverse effects include nausea, fatigue, emesis, diarrhea, decreased appetite, headache, neutropenia, anemia, and thrombocytopenia, with pooled clinical trials demonstrating 87% of patients developing decreased hemoglobin. The link between olaparib-induced macrocytic anemia and folate deficiency was first described in a patient with ovarian cancer, which improved with folic acid supplementation. This observation was expanded in a retrospective case series (Shammo et al, 2019). Subsequently, we sought to prospectively evaluate the prevalence and timing of folate deficiency in patients receiving olaparib and evaluate the effect of folic acid supplementation.
Methods:
This is a single center prospective study of patients with advanced stage breast or ovarian cancer treated with olaparib to determine the frequency and timing of folate deficiency in patients with solid tumors. Patients who developed grade 1 anemia (Hgb &lt; 12.0 g/dL) and folate deficiency were randomized to receive placebo or folate supplementation. All patients who developed folate deficiency and grade 2 anemia (Hgb &lt; 10g/dL) were started on folic acid supplementation. All enrolled patients were continued on olaparib until disease progression. Complete blood counts and folate levels were obtained biweekly for the first three months, then monthly for six months. Serum folate levels were evaluated at baseline and one month after olaparib completion or discontinuation. Patients were excluded if they had previously received therapy with olaparib or other PARP inhibitors.
Results:
10 female patients were consented to the trial from August 2020 to August 2022. 9 subjects were enrolled. 1 subject was excluded due to previous PARP inhibitor treatment. Of the 9 patients enrolled, 5 patients identified as black, 1 identified as Asian, and 3 identified as non-hispanic, white. The median age was 62 years. 5 patients received olaparib for ovarian cancer and 4 patients received olaparib for breast cancer. All patients were receiving olaparib as maintenance, adjuvant, or second line therapy. 8 of 9 patients developed folate deficiency while on olaparib. Mean folate nadir value while on olaparib amongst all 9 subjects was 3.96 ng/mL (range 1.7 -10.2, standard deviation [SD] = 2.69 ng/mL). Of the patients who developed folate deficiency, mean time until diagnosis of folate deficiency was 6.25 weeks (range 4-10, SD = 2.50 weeks). All cases of folate deficiency were identified within 3 months of olaparib initiation. The only patient who did not develop folate deficiency had the highest baseline folate level at 35 ng/mL, whereas the other patients demonstrated a median baseline serum folate of 13.2 ng/mL. Interestingly, the onset of folate deficiency itself did not correlate with a clinically meaningful drop in Hgb level (greatest Hgb drop was 1.1 g/dL) When patients were randomized to receive folic acid supplementation, folate levels promptly normalized.
Conclusions:
We discovered that folate deficiency occurred in nearly all patients who were started on olaparib for breast or ovarian cancer within weeks of initiating olaparib. Folate levels normalized with supplementation and improved with discontinuation of olaparib therapy, but deficiencies did not result in a clinically significant difference in hemoglobin levels which may have been related to frequent Hgb monitoring and the specified trial intervention with folic acid supplementation. Further studies are needed to further investigate the role of PARP inhibition in erythropoiesis and the folate pathway.