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Updated: Jan 15, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Niraparib and abiraterone acetate plus prednisone for HRR-deficient metastatic castration-sensitive prostate cancer:
Gerhardt Attard1, Neeraj Agarwal2, Julie N Graff3,4
1Cancer Institute, University College London, London, UK. g.attard@ucl.ac.uk.
Abstract:
Inhibition of poly(ADP-ribose) polymerase (PARP) after relapse on hormone therapy is well established for patients with prostate cancer with homologous recombination repair (HRR) gene alterations, but resistance often develops. We hypothesized that PARP inhibition within 6 months of starting androgen deprivation therapy for metastatic castration-sensitive prostate cancer (mCSPC) could be effective and improve radiographic progression-free survival when added to standard-of-care treatments. The double-blind AMPLITUDE trial evaluated combining niraparib, a potent and specific PARP inhibitor, with abiraterone acetate and prednisone (AAP) versus placebo and AAP in mCSPC with HRR gene alterations. Patients (n = 696) were randomized in a 1:1 ratio (348 per group). Median age was 68 years; 56% had BRCA1 or BRCA2 alterations; 78% had high-volume metastases; and 16% had received docetaxel. The primary endpoint was met, with a significant improvement in radiographic progression-free survival observed first in the BRCA subgroup (median not reached at the time of analysis for the niraparib and AAP group versus 26 months for the AAP group; hazard ratio = 0.52; 95% confidence interval: 0.37-0.72; P < 0.0001) and then in the intention-to-treat population (hazard ratio = 0.63; 95% confidence interval: 0.49-0.80; P = 0.0001). The data for overall survival, a key secondary endpoint, are immature (193/389 events) but favor niraparib (hazard ratio = 0.79 (95% confidence interval: 0.59-1.04); BRCA subgroup: hazard ratio = 0.75 (95% confidence interval: 0.51-1.11)). Incidence of grade 3 or 4 adverse events was 75% in the niraparib and AAP group and 59% in the AAP group; most frequent in the niraparib and AAP group were anemia (29%), with 25% of patients requiring a blood transfusion, and hypertension (27%). There were 14 treatment-emergent adverse events leading to deaths in the niraparib group and seven in the placebo group. Combining niraparib with AAP significantly improved radiographic progression-free survival in patients with mCSPC harboring BRCA1/BRCA2 or other HRR gene alterations, suggesting clinical benefit with this combination for these patients. ClinicalTrials.gov identifier: NCT04497844 .
Insights
Adding niraparib to abiraterone acetate and prednisone significantly improved radiographic progression-free survival for men with metastatic castration-sensitive prostate cancer and HRR gene alterations. This combination therapy offers a new treatment option for these patients.
Area of Science:
- Oncology
- Genitourinary Cancers
- Prostate Cancer Research
Background:
- Hormone therapy resistance is common in advanced prostate cancer.
- Poly(ADP-ribose) polymerase (PARP) inhibitors show efficacy in prostate cancer with HRR gene alterations.
- Early PARP inhibition in metastatic castration-sensitive prostate cancer (mCSPC) is under investigation.
Purpose of the Study:
- To evaluate the efficacy of combining niraparib with abiraterone acetate and prednisone (AAP) in mCSPC patients with HRR gene alterations.
- To assess the impact on radiographic progression-free survival (rPFS) compared to AAP alone.
Main Methods:
- The AMPLITUDE trial was a double-blind study randomizing 696 mCSPC patients with HRR alterations to niraparib + AAP or placebo + AAP.
- Patients were randomized 1:1.
- Primary endpoint was rPFS.
Main Results:
- Niraparib + AAP significantly improved rPFS in the BRCA subgroup (HR=0.52) and the overall HRR-altered population (HR=0.63).
- Median rPFS was not reached in the niraparib arm for BRCA patients vs. 26 months for placebo.
- Overall survival data are immature but favor niraparib.
Conclusions:
- Combining niraparib with AAP demonstrates significant clinical benefit by improving rPFS in mCSPC patients with HRR gene alterations.
- This combination represents a promising therapeutic strategy for this patient population.
