The phase 3 AMPLITUDE trial (NCT04497844) is the first trial to demonstrate the efficacy of the combination of niraparib (Zejula) plus abiraterone acetate (Zytiga) and prednisone (AAP) in patients with metastatic castration-sensitive prostate cancer (mCSPC) with homologous recombination repair (HRR) alterations, making it a really important study for this population, according to Dana E. Rathkopf, MD.
In the intention-to-treat (ITT) population (HRRm), niraparib plus AAP and androgen deprivation therapy (ADT; n = 348) significantly reduced the risk of radiographic progression or death by 37% vs placebo plus AAP and ADT (n = 348); the median radiographic progression-free survival (rPFS) in the respective arms was not estimable (NE) and 29.5 months (HR, 0.63; 95% CI, 0.49-0.80; P = .0001).1 In the BRCA-mutant subgroup, the niraparib regimen (n = 191) reduced the risk of radiographic progression or death by 48% vs placebo plus AAP (n = 196); in the respective arms, the median rPFS was NE and 26.0 months (HR, 0.52; 95% CI, 0.37-0.72; P < .0001).
The niraparib regimen also significantly reduced the risk of symptomatic progression by 50% vs placebo plus AAP in the HRRm population (HR, 0.50; 95% CI, 0.36-0.69; P < .0001). In the BRCA-mutated subgroup, niraparib plus AAP reduced the risk of symptomatic progression by 56% vs the placebo regimen (HR, 0.44; 95% CI, 0.29-0.68; P = .0001).
“The AMPLITUDE trial is one of the most significant studies to be presented at [the 2025] ASCO [Annual Meeting]. It offers a new treatment paradigm for our patients who tend to have a worse prognosis, in a targeted way,” Rathkopf said in an exclusive interview with OncLive®. “It is the first trial to show a benefit of this combination of a PARP inhibitor, niraparib, plus AAP in mCSPC, and I think that this will be immediately translatable to the patient populations in our communities that are in need of better options.”
In the interview, Rathkopf, who is a genitourinary medical oncologist, attending physician, and chief of Research Council at Memorial Sloan Kettering Cancer Center, in New York, New York, discussed the study in detail—offering insight into the trial design, patient population, efficacy and safety data, and the implications of the research for the field.
OncLive: What is the rationale for AMPLITUDE, and how does it build upon existing knowledge of PARP inhibitors in prostate cancer?
Rathkopf: This is the first phase 3 trial to show efficacy of a PARP combination with an androgen receptor pathway inhibitor in mCSPC. We know that patients who have HRR mutations tend to have a worse prognosis, so we’re constantly trying to look for therapies, particularly targeted therapies, that can improve outcomes for these patients. In the metastatic castration-resistant setting, the combination of niraparib plus abiraterone demonstrated improvement in terms of rPFS for that patient population. Therefore, we decided to test this in an earlier [setting], looking at patients [with] mCSPC in the phase 3 AMPLITUDE study.
What is the study design? What were the key objectives of the AMPLITUDE study?
This was a phase 3 study looking at patients with mCSPC who had mutations in HRR genes. [This] was designed as a phase 3, randomized, placebo-controlled, blinded study. There [was a] 1:1 randomization, [with patients] stratified based on prior docetaxel, volume of disease, and the type of HRR mutation [that they had]. Patients received either niraparib plus AAP with ADT or placebo plus AAP with ADT. The primary end point was rPFS.
What were the key efficacy results observed with niraparib plus AAP?
The primary end point for this study, after 30.8 months [of] median follow-up, was rPFS, and this favored the combination arm of niraparib, AAP, and ADT. There was a 48% reduction in time to radiographic progression for this population of BRCA-mutated patients, and a 37% reduction in the ITT population of all HRR alterations that were tested in this study.
What was learned about the safety of niraparib plus AAP?
There were no new safety signals seen with this combination. [Adverse effects (AEs)] were similar to [what was observed with] the combination in metastatic castration-resistant prostate cancer. The most common grade 3 and 4 treatment-related AEs were anemia and hypertension. The [rate of treatment-emergent AEs] leading to [treatment discontinuation] was 15% [with] the [niraparib] combination and only 10% [with] the placebo [combination].
What are the clinical implications of the AMPLITUDE trial in mCSPC, and how could these data influence the treatment paradigm?
This is a really important study for this patient population. This is a patient population that tends to have a worse prognosis due to their HRR alteration status. [As such,] to be able to offer patients with newly diagnosed mCSPC a targeted option combining a PARP inhibitor such as niraparib with abiraterone and prednisone that can improve time to radiographic progression [and] also improve time to symptomatic progression—which was a secondary end point—and [also have it be] well tolerated, is an opportunity for these patients to do well and maximize their outcomes.
