Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial
Mené sur 289 patients atteints d'un cancer métastatique de la prostate résistant à la castration et présentant des anomalies au niveau de gènes impliqués dans la réparation des dommages causés à l'ADN (durée médiane de suivi : 10 mois), cet essai multicentrique de phase II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité du niraparib
Background : Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition ofPARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDswho progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods : In this multicentre, open-label, single-arm, phase 2 study, patients aged at least18 years with histologically confirmed metastatic castration-resistant prostate cancer(mixed histology accepted, with the exception of the small cell pure phenotype) andDRDs (assessed in blood, tumour tissue, or saliva), with progression on a previousnext-generation androgen signalling inhibitor and a taxane per Response EvaluationCriteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an EasternCooperative Oncology Group performance status of 0–2, were eligible. Enrolled patientsreceived niraparib 300 mg orally once daily until treatment discontinuation, death,or study termination. For the final study analysis, all patients who received at leastone dose of study drug were included in the safety analysis population; patients withgermline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint wasobjective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings : Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182(63%) had received three or more systemic therapies for prostate cancer. 223 (77%)of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3),the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, themost common treatment-emergent adverse events of any grade were nausea (169 [58%]of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 orworse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at leastone serious treatment-emergent adverse event, the most common were also haematological(thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fataloutcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation : Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patientswith metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations.
The Lancet Oncology 2022