PARP Inhibitors in mCRPC Linked to High Risk of Hematological AEs

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An increased risk of hematological adverse events (AEs), including anemia, thrombocytopenia, and neutropenia, was observed when poly ADP ribose polymerase inhibitors (PARPi) were administered as part of a treatment regimen for patients with metastatic castration-resistant prostate cancer (mCRPC), according to a systematic review and meta-analysis of data from 8 phase 2 and 3 randomized clinical trials.1

PARPi use demonstrated an increased risk of all-grade anemia (risk ratio [RR], 3.37; 95% CI, 2.37-4.79; P =.00001), thrombocytopenia (RR, 4.54; 95% CI, 1.97-10.44; P =.0004), and neutropenia (RR, 3.11; 95% CI, 1.60-6.03; P =.0008). There were also increased risks observed for high-grade anemia (RR, 6.94; 95% CI, 4.06–11.86; P <.00001) and thrombocytopenia (RR, 5.52; 95% CI, 2.80–10.88; P <.00001).

“While PARPis have shown favorable clinical impacts on [prostate cancer] survival, they do come with adverse effects on bone marrow and often necessitate subsequent blood replacement therapies…Further, since PARPis are reserved for those with advanced disease, physicians must emphasize a balance between therapeutic benefit and potential effect of AEs on the patient’s quality of life. The primary strength of this study lies in its dedicated evaluation of hematological AEs in mCRPC, which may inform the above PARPi considerations,” study authors wrote in findings published in Cancers.

The 8 trials in mCRPC included in the meta-analysis were:

• The phase 2 PROpel II and phase 3 PROpel III (NCT03732820) trials investigating olaparib (Lynparza) plus abitaterone (Zytiga) as a first-line therapy;
• The phase 2 NCI 9012 trial (NCT01576172) investigating abiraterone and prednisone with or without veliparib (ABT-888);
• The phase 3 KEYLYNK-010 trial (NCT03834519) of pembrolizumab (Keytruda) plus olaparib vs abiraterone or enzalutamide (Xtandi);
• The phase 3 MAGNITUDE trial (NCT03748641) of abiraterone and prednisone with or without niraparib (Zejula);
• The phase 3 PROfound trial (NCT02987543) of olaparib vs enzalutamide vs abiraterone;
• The phase 3 TALAPRO-2 (NCT03395197) of talazoparib (Talzenna) and enzalutamide vs talazoparib monotherapy;
• And the phase 3 TRITON3 trial (NCT02975934) of rucaparib (Rubraca) vs physician’s choice of therapy in patients with a homologous recombination gene deficiency.

All 8 studies were evaluable for anemia AEs. The incidence of all-grade anemia in the PARPi cohorts was 48.7%, and the incidence of high-grade anemia was 24.9% Five studies could be evaluated for thrombocytopenia outcomes, and the incidences for all-grade and high-grade thrombocytopenia were 16.9% and 3.70%, respectively, in the PARPi cohorts. Four studies were evaluable for neutropenia outcomes and showed that all-grade neutropenia incidence was 18.14% and high-grade neutropenia incidence was 11.36%.

Niraparib demonstrated the lowest RR for all hematological AEs, with a RR for anemia of 2.27, thrombocytopenia of 2.49, and neutropenia of 0.008. The lowest RRs for anemia (2.44) and thrombocytopenia (2.49) were observed in combination with abiraterone.

All of the studies were published between 2017 and 2023. A collective 3904 patients were enrolled in these studies; 2218 were administered a PARPi and 1686 were administered a placebo or other cancer treatment. Across the patients who were treated with a PARPi, 15.1% (n = 323) discontinued treatment (not including NCI 9012) and 32.4% (n = 522) reduced their dose (not including NCI 9012 and KEYLYNK-010), due to an AE.

The findings from this meta-analysis echo other studies evaluating hematologic AEs when using PARPis in additional cancer types. A 2021 meta-analysis of PARPi use across multiple cancer types found an increased risk of all-grade anemia (RR, 2.32; 95% CI, 1.78-3.01; P <.0000), neutropenia (RR, 1.69; 95% CI, 1.38-2.07; P <.00001), and thrombocytopenia (RR, 2.54; 95% CI, 1.87-3.45; P <.00001) when PARPis were administered vs other cancer treatments.2 Further, the risk of high-grade hematological AEs was also significantly increased, and all 5 of the investigated PARPis were associated with a significant increased risk of anemia.

REFERENCES:
1. Bowling GC, Swargaloganathan P, Heintz C, et al. Hematological toxicities with PARP inhibitors in prostate cancer: A systematic review and meta-analysis of phase II/III randomized controlled trials. Cancers (Basel). 2023;15(19):4904. Published 2023 Oct 9. doi:10.3390/cancers15194904

2. Wang C, Li J. Haematologic toxicities with PARP inhibitors in cancer patients: an up-to-date meta-analysis of 29 randomized controlled trials. J Clin Pharm Ther. 2021;46(3):571-584. doi:10.1111/jcpt.13349