Although poly (ADP-ribose) polymerase (PARP) inhibitors interfere with DNA repair processes, leading to warnings in terms of risk for developing second primary malignancies, findings from a systematic review and safety meta-analysis of placebo-controlled randomized studies are reassuring for patients starting PARP inhibitors in the first-line setting. The results of the analysis, published by Morice et al in Annals of Oncology, show that there is no increased risk of developing second primary malignancies.
Researchers systematically reviewed placebo-controlled randomized clinical studies involving PARP inhibitors administered in adult patients. They selected 23 placebo-controlled randomized studies involving 8,857 patients, of whom 5,492 patients (62%) were randomly assigned to the PARP inhibitor arms and 3,365 patients (38%) were in the placebo arms.
Overall, 51 second primary malignancies were reported in patients in the PARP inhibitor arms (0.9%) and 24 second primary malignancies were reported in placebo arms (0.7%). Exposure to PARP inhibitors was not associated with an increased risk of developing second primary malignancy vs placebo, with a median follow-up ranging from 3.8 to 78 months (Peto odds ratio = 1.13, 95% confidence interval [CI] = 0.70–1.83, P = .62), with no heterogeneity across studies.
According to the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium tool, all 23 studies included in that analysis were rated as having unclear risk of bias.
Although the study team acknowledged several limitations of their analysis—such as being conducted at study level, nonavailability of individual safety data, use of pooled data from studies with different length of follow-up, and inclusion of patients with initial and relapsed cancers—the authors concluded that their findings do not suggest a need for additional close monitoring of patients treated with PARP inhibitors in terms of risk for developing a second primary malignancy.
Analysis of Patients With Hematologic Malignancies
In another letter to the editor published by Martin et al in the same issue of the Annals of Oncology, a group of researchers reported findings from a series of 20 retrospectively identified patients with myelodysplastic syndromes or acute myeloid leukemia occurring during or after administration of PARP inhibitors. They wrote that their data support the hypothesis that PARP inhibitors may act by exerting a selective pressure that boosts clonal expansion, especially TP53 and PPM1D mutations.
The team aimed to describe the prevalence and evolution of clonal hematopoiesis and therapy-related myeloid neoplasms following treatment with PARP inhibitors in patients with ovarian cancer to better understand the molecular mechanisms underlying development of hematological disease. In addition to the safety meta-analysis of randomized controlled studies described above, their analysis followed a retrospective study of the World Health Organization pharmacovigilance database, published earlier this year by Morice et al in The Lancet Haematology, which indicated an increased risk of therapy-related myeloid neoplasms after administration of PARP inhibitors.
In the series of 11 patients with secondary myelodysplastic syndromes and 9 patients with secondary acute myeloid leukemia, median duration of previous treatment with PARP inhibitors was 17 months (range = 3–57). Therapy-related myeloid neoplasms occurred 2 years (range = 0.4–4.8) after initiation of PARP inhibition and 1.6 months (range = 0.4–17.6) after discontinuation of the therapy.
All patients had unfavorable karyotypes, of which 19 of 20 (95%) had complex karyotypes and 10 of 12 (83%) harbored mutations in the DDR genes. Despite 11 patients (55%) with ovarian cancer being in complete remission, median overall survival was 4.3 months.
The study team further identified 36 patients with ovarian cancer with or without maintenance PARP inhibitor treatment who were free of hematological disease to compare occurrence of clonal hematopoiesis. Median duration of treatment with PARP inhibitors was 11.2 months (range = 0.4–45.8), and median time between initiation of PARP inhibition and next-generation sequencing was 8.5 months (range = 1.1–15.6). No significant differences in terms of patient characteristics were found between the two groups.
Clonal hematopoiesis was found in 14 of 18 patients (78%) who received maintenance treatment, compared to 7 of 18 patients (39%) without maintenance PARP inhibition (P = .018). Twelve patients (67%) treated with PARP inhibitors harbored mutations in the DDR pathway compared to 3 of 18 patients (16.7%) without maintenance PARP inhibitor treatment (P = .002). The study team sequenced nine paired specimens before and after treatment with PARP inhibitors, showing that mutations emerged or expanded during the course of therapy.
The authors commented that the clinical benefit of maintenance treatment with PARP inhibitors for ovarian cancer is not questionable, but their data raise the question of identification and potential preventive strategies in patients who are considered at high risk of developing therapy-related myeloid neoplasms.
Disclosure: For full disclosures of the study authors, visit annalsofoncology.org.
