In the phase II GALAHAD trial reported in The Lancet Oncology, Matthew R. Smith, MD, and colleagues found that the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib showed activity in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects whose disease had progressed on previous androgen-signaling inhibitor and taxane therapy, particularly among those with BRCA alterations.
Matthew R. Smith, MD
Study Details
The open-label trial included 289 patients (safety population) enrolled from sites in 15 countries between September 2016 and June 2020. They received niraparib at 300 mg orally once daily until disease progression or unacceptable toxicity/adverse events. Of these, 66 patients were excluded from efficacy analysis due to biomarker assay findings of monoallelic or nonpathogenic mutations.
A total of 223 patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort, n = 142) or biallelic alterations in other prespecified DNA repair gene defects (non-BRCA cohort, n = 81) were included in the overall efficacy analysis population. Measurable disease was present in 76 of 142 patients in the BRCA cohort (measurable BRCA cohort) and in 47 of 81 patients in the non-BRCA cohort. The primary outcome measure was objective response rate in the measurable BRCA cohort.
Responses
At final analysis, with a median follow-up of 10.0 months (interquartile range [IQR] = 6.6–13.3 months), objective response was observed in 26 (34.2%, 95% confidence interval [CI] = 23.7%–46.0%) of 76 patients in the measurable BRCA cohort, with complete response in 2 (3%). A ≥ 30% decrease in the sum of longest target lesion diameters was observed in 35 patients (46%).
Median duration of response was 5.55 months (95% CI = 3.91–7.20 months), with 8 (31%) of 26 responses ongoing at the data cutoff (January 2021). In the entire BRCA cohort, event-free survival at 12 and 24 months was 56.4% (95% CI = 47.2%–64.6%) and 15.2% (95% CI = 7.7%–25.1%); median radiographic progression–free survival was 8.08 months (95% CI = 5.55–8.38 months), and median overall survival was 13.01 months (95% CI = 11.04–14.29 months).
At a median follow-up of 8.6 months (IQR = 4.8–14.0 months) in the measurable non-BRCA cohort, objective responses (all partial) were observed in 5 (10.6%, 95% CI = 3.5%–23.1%) of 47 patients. In the entire non-BRCA cohort, event-free survival at 12 and 24 months was 41.3% (95% CI = 30.0%–52.2%) and 11.1% (95% CI = 4.4%–21.2%), median radiographic progression–free survival was 3.71 months (95% CI = 1.97–5.49 months), and median overall survival was 9.63 months (95% CI = 8.05–13.44 months).
Adverse Events
Among the 289 patients in the safety population, the most common adverse events of any grade were nausea (58%), anemia (54%), and vomiting (38%). Grade ≥ 3 adverse events occurred in 75% of patients, most commonly anemia (33%), thrombocytopenia (16%) and neutropenia (10%). Serious adverse events occurred in 46% of patients, most commonly thrombocytopenia (6%) and anemia (4%). Two deaths were considered possibly related to study treatment, due to urosepsis in one patient in the BRCA cohort and sepsis in another patient in the non-BRCA cohort.
The investigators concluded, “Niraparib is tolerable and shows antitumor activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DNA repair gene defects, particularly in those with BRCA alterations.”
Dr. Smith, of Massachusetts General Hospital Cancer Center, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Janssen Research & Development. For full disclosures of the study authors, visit thelancet.com.
