Individualized starting dosage of niraparib improves safety with comparable effectiveness

24.05.2023 17:25

Individualized starting dosage depending on body weight and platelet count shows fewer hematological adverse events compared to fixed starting dosage with comparable effectiveness of niraparib in 1L maintenance therapy of ovarian cancer. [1] Confirmation of the results of the phase III PRIMA study by Chinese PRIME study. [2]

The PARP inhibitor (PARP: poly-[ADP-ribose] polymerase) niraparib (Zejula) demonstrated a durable and clinically relevant benefit in terms of progression-free survival (PFS) as maintenance therapy in patients in the pivotal phase III PRIMA study with newly diagnosed advanced ovarian cancer that had responded to first-line platinum-based chemotherapy. [1] The subsequent introduction of an individualized starting dosage (ISD) depending on body weight and/or platelet count at the start of treatment before the start of therapy improved tolerability with comparable effectiveness compared to the fixed starting dosage (FSD) of 300 mg. [1] This is shown by a prospective analysis of PRIMA data that was recently published in the journal Cancer. [1] These results are confirmed by data from the Chinese phase III PRIME trial presented at the annual meeting of the Society of Gynecologic Oncology (SGO) in late March 2023. [2]

Subsequent introduction of the individualized starting dosage in the PRIMA study

In the PRIMA study, 733 patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy were initially treated with a fixed starting dose (FSD) of 300 mg once daily (niraparib or placebo). [1]

During the recruitment phase, the study protocol was adjusted based on findings from a post-hoc analysis of the NOVA study, in which niraparib was investigated in recurrent ovarian cancer. Patients newly enrolled in the PRIMA study then received an individualized starting dosage (ISD): [1]
– Patients with a body weight <77 kg and/or a platelet count <150,000/μl started with niraparib 200 mg once daily. [1]
- Patients with a body weight ≥ 77 kg and a platelet count ≥ 150,000/μL received niraparib 300 mg once daily. [1]
35.2 % patients received an ISD and 64.8 % received an FSD. [1] This allowed a prospective comparison of efficacy and safety depending on the starting dosage. [1] The efficacy of niraparib, as determined by the primary endpoint of progression-free survival (PFS), at the individual and fixed starting doses was comparable in the overall population and in the homologous recombination deficiency (HRd) population: [1]
– Hazard ratio (HR) of PFS in the overall population: ISD-HR, 0.69 [95% confidence interval (CI), 0.48-0.98)] vs. FSD-HR, 0.59 (95% CI , 0.46-0.76) [1]
– HR of PFS in the HRd population: ISD-HR, 0.39 (95%-CI, 0.22-0.72) vs. FSD-HR, 0.44 (95%-CI, 0.30-0, 64) [1]

Fewer hematological AEs due to individualized starting dosage

In patients with low body weight (<77 kg) and/or low platelet counts (<150,000/μL) at baseline who received an individualized starting dose, the rates of ≥Grade 3 hematologic adverse events (AEs), dose interruptions and dose reductions were lower in patients who received FSD. [1] The incidences for thrombocytopenia were 17.2 % vs. 51.9 %, for anemia 20.5 % vs. 35.0 % and for neutropenia 14.8 % vs. 27.2 % (each ISD vs. FSD). [1] The rate of dose interruptions due to AEs was 64.8 % (ISD) vs. 85.2 % (FSD) and the rate of dose reductions was 56.6 % (ISD) vs. 79.8 % (FSD) . [1]

Chinese phase III study confirms PRIMA study results

These results are confirmed by the results of the Chinese PRIME study with a total of 384 patients with newly diagnosed ovarian cancer. in which the patients received the ISD from the beginning according to the study protocol (n = 255 in the niraparib group). There were lower incidences of treatment-emergent adverse events (TEAEs) ≥ grade 3 as well as dose interruptions and reductions due to TEAEs than in previous niraparib studies, even if the studies are not directly comparable due to different study populations. [3] According to an exploratory analysis presented at the SGO Annual Meeting in March, there is no evidence that dose modifications due to TEAEs limit the effectiveness of niraparib maintenance therapy. [2] In the overall population, the median PFS for patients whose dose was reduced due to TEAEs was 27.6 months versus 24.8 months for patients who maintained the original dose (HR 0.89; 95% -CI 0.61-1.30).[2]

credentials
[1] Mirza MR et al. Cancer 2023; 1-10. doi: 10.1002/cncr.34706
[2] Zhu J et al. Poster presentation at the Society of Gynecologic Oncology (SGO) Annual Meeting on Women's Cancer 2023, 25-28 March 2023, Tampa, Florida, USA. Poster #198
[3] Li N et al. Presentation at the Society of Gynecologic Oncology (SGO) Annual Meeting on Women's Cancer; 18-21 March 2022; Phoenix. Arizona, USA.