Fuzuloparib: First Approval

Inhibition of the PARP1 enzyme with fuzuloparib was comparable with olaparib (PARP1 IC₅₀ 1.46 nM with fuzuloparib and 1.34 nM with olaparib) when measured using ELISA [4]. Both fuzuloparib and olaparib inhibited BRCA1 or BRCA2-deficient lung fibroblast, ovarian cancer and breast cancer cell lines in cell culture experiments (IC₅₀ 0.053–1.57 µM with fuzuloparib and 0.035–2.16 µM with olaparib); though no relevant inhibition of BRCA1 or BRCA2-positive cell lines were observed with both inhibitors (IC₅₀ > 10 µM with both inhibitors). In animal studies, fuzuloparib 30 mg/kg and olaparib 30 mg/kg inhibited the growth of BRCA1-negative breast cancer in mice (day 21 inhibition rate 59% with fuzuloparib and 44% with olaparib). Neither PARP inhibitor was associated with significant differences in body weight compared with placebo treated mice [4].

PARP inhibition is known to induce embryo-foetal toxicity in animal studies, and fuzuloparib may cause foetal harm in pregnant women. Contraception is recommended in women of childbearing age during treatment and for 6 months after the last dose of fuzuloparib [3].

A dose-proportional increase in the AUC_0–t and C_max of fuzuloparib occurs across a dose range of 10–150 mg when administered as a single dose. The accumulation ratio (in AUC_0–t) after 13 days is 1.86 in patients receiving fuzuloparib 150 mg twice daily. The administration of fuzuloparib after a high-fat meal does not have a significant effect on the AUC, though the t_max is delayed from 3 h to 6 h. The apparent volume of distribution of fuzuloparib is 34.6 L. Plasma binding of fuzuloparib is 74.3–81.6% over a concentration range of 20–2000 ng/mL. The terminal half-life of fuzuloparib is 9.14 h in patients administered multiple doses of fuzuloparib 150 mg twice daily. Fuzuloparib is predominantly metabolised by CYP3A4, with the most common metabolites being mono-oxidation and subsequently hydrogenated products; each metabolite contributes < 10% of the total plasma radioactivity. 44.2% and 59.1% of the radioactivity from the original dose is excreted into the faeces and urine. 15.8–16.8% of the original dose is excreted as unchanged fuzuloparib in urine [3].

Concomitant administration of itraconazole (strong CYP3A4 inhibitor) increases the C_max, AUC_0–t and AUC_∞ of fuzuloparib by 51.0%, 325% and 381%, respectively; increases of 32.4%, 104.5% and 109.6%, respectively, are observed with fluconazole (moderate CYP3A4 inhibitor). Induction of CYP3A4 by rifampicin decreases the C_max, AUC_0–t and AUC_∞ of fuzuloparib to 32.0%, 10.4%, and 10.4%, respectively. Inhibition of the CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes by fuzuloparib poses a low risk for drug–drug interactions, and no drug–drug inhibition studies are required according to relevant guidelines. Fuzuloparib may induce CYP1A2, CYP2B6 and CYP3A4 at a concentration of 5 µM, based on data from in vitro studies. Clinical studies to investigate the induction of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4 by fuzuloparib are ongoing. Fuzuloparib is not recommended in patients with moderate or severe hepatic impairment or renal impairment as data are not yet available in these patient populations. Mild hepatic impairment and mild renal impairment does not cause relevant changes in clearance of fuzuloparib [3].

Safety data on monotherapy with fuzuloparib 150 mg twice daily were collected from three studies that enrolled a total of 294 patients with ovarian cancer [3]. All-grade AEs were reported in 94.9% of patients, with the most common AEs with an incidence ≥ 40% being anaemia (58.5% of patients), nausea (57.1%), leukopenia (54.4%), fatigue (43.5%) and thrombocytopenia (41.5%). The most common grade ≥ 3 AEs with an incidence ≥ 2% were haematological AEs; anaemia (25.5%), thrombocytopenia (13.3%), neutropenia (10.5%), leukopenia (9.9%) and lymphocytopenia (5.1%). The overall incidence of grade ≥ 3 haematological AEs was 40.5%. Dose interruption or reduction were required in some patients due to anaemia (dose interruption in 23.1% of patients and dose reduction in 9.2% of patients), thrombocytopenia (13.9% and 6.5%), neutropenia (8.8% and 2.0%), leukopenia (9.5% and 3.4%) and lymphocytopenia (2.0% and 0.7%). Monitor complete blood count at baseline then every fortnight for three months after initiating treatment and regularly afterwards. Consult local prescribing information for recommendations on dose reduction or interruption. Cases of myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) have been reported during clinical trials in other PARP inhibitors used for the treatment of cancer. If signs and symptoms of MDS or AML are observed, discontinue fuzuloparib treatment and administer appropriate therapy [3].

Gastrointestinal AEs have been reported with fuzuloparib, with an overall all-grade incidence of 72.8% (2.4% for grade ≥ 3). The incidence of all-grade nausea was 57.1% (0.3% for grade ≥ 3) and 26.2% (1.4% for grade ≥ 3) for vomiting. Grade ≥ 2 nausea and vomiting may be managed with dose interruption, dose reduction and/or antiemetic medications [3].

Three trials are evaluating fuzuloparib in metastatic castration-resistant prostate cancer, NCT04691804 for combination therapy as a first-line treatment (phase III; fuzuloparib plus abiraterone acetate and prednisone vs placebo plus abiraterone acetate and prednisone), NCT04869488 for combination therapy or monotherapy in patients who failed prior treatment with abiraterone/enzalutamine and with or without homologous recombination repair gene mutations (phase II; fuzuloparib with/without apatinib vs abiraterone/enzalutamine plus prednisone) and NCT04102124 for combination therapy in patients who did not respond to abiraterone and docetaxel treatment (phase II; fuzuloparib plus rezvilutamide vs rezvilutamide plus placebo vs placebo).

Other trials of fuzuloparib includes NCT04296370 in patients with HER2-negative metastatic breast cancer with gBRCAm who received no more than two lines of chemotherapy, received prior therapy with an anthracycline and a taxane and did not respond to one endocrine therapy or are not candidates for endocrine therapy (phase III; fuzuloparib with/without apatinib vs chemotherapy) and NCT04400188 combination therapy in patients with relapsed small cell lung cancer who failed at least one line of platinum-based chemotherapy (phase I/II; fuzuloparib plus temozolomide with/without adebrelimab).