12 hours ago
Add-On Niraparib May Slow mHSPC
Adding the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib to abiraterone acetate plus prednisone delayed disease progression and postponed the onset of symptoms in patients with metastatic castration-sensitive prostate cancer with homologous recombination repair (HRR) genetic alterations, according to findings from the AMPLITUDE trial.
An interim analysis also demonstrated an early trend toward improved overall survival in patients who received niraparib.
These findings support adding niraparib to abiraterone acetate plus prednisone 'as a new treatment option' in patients with HRR alterations, said Study Chief Gerhardt Attard, MD, PhD, chair of medical oncology, University College London Cancer Institute, London, England, speaking at the American Society of Clinical Oncology (ASCO) 2025 annual meeting.
The findings also highlight that 'it's going to be incredibly important that patients who get diagnosed with hormone-sensitive prostate cancer are tested to see if they have these mutations, so they can be offered the right therapy at the right time,' Outside Expert Bradley McGregor, MD, with Dana-Farber Cancer Institute in Boston, said during a press briefing.
Ultimately, 'you don't know if you don't test,' McGregor added.
About one quarter of patients with metastatic castration-sensitive prostate cancer have alterations in HRR genes, about half of which are BRCA mutations. These patients typically experience faster disease progression and worse outcomes. An androgen receptor pathway inhibitor, such as abiraterone, alongside androgen deprivation therapy with or without docetaxel, is standard therapy for these patients, but 'there is still a need for treatments that are tailored to patients whose tumors harbor HRR alterations,' Attard said in a press release.
Adding niraparib to this standard regimen could help improve survival in these patients.
In 2023, the FDA approved niraparib and abiraterone acetate to treat BRCA -mutated metastatic castration-resistant prostate cancer, after findings from the MAGNITUDE study demonstrated improved progression-free survival (PFS).
The phase 3 AMPLITUDE trial set out to evaluate whether this combination would yield similar survival benefits in metastatic castration-sensitive prostate cancer with HRR mutations.
In the study, 696 patients (median age, 68 years) with metastatic castration-sensitive prostate cancer and one or more HRR gene alterations were randomly allocated (1:1) to niraparib with abiraterone acetate plus prednisone or placebo with abiraterone acetate plus prednisone.
Exclusion criteria included any prior PARP inhibitor therapy or androgen receptor pathway inhibitor other than abiraterone. Eligible patients could have received at most 6 months of androgen deprivation therapy, ≤ 6 cycles of docetaxel, ≤ 45 days of abiraterone acetate plus prednisone and palliative radiation.
Baseline characteristics were well balanced between the groups. Just over half the patients in each group had BRCA1 or BRCA2 alterations. The majority had an electrocorticogram performance status of 0, but high-risk features with a predominance for synchronous metastatic disease and metastatic high volume. About 16% had received prior docetaxel, in keeping with real world data, Attard noted.
At a median follow-up of 30.8 months, niraparib plus standard therapy led to a significant 37% reduction in the risk for radiographic progression or death. The median radiographic PFS (rPFS) was not reached in the niraparib group vs 29.5 months in the placebo group (hazard ratio [HR], 0.63; P = .0001).
Patients with BRCA alterations, in particular, showed the greatest benefit, with niraparib reducing the risk for radiographic progression or death by 48% compared to placebo (median rPFS not reached vs 26 months; HR, 0.52; P < .0001).
On the key secondary endpoint of time to symptomatic progression, adding niraparib led to a 'statistically and clinically' significant benefit — a 50% lower in the risk for symptomatic progression in the full population (HR, 0.50), and a 56% lower risk in BRCA -mutant group (HR, 0.44).
The first interim analysis also showed an early trend toward improved overall survival favoring the niraparib combination, with a reduction in the risk for death of 21% in the HRR-mutant population (HR, 0.79; P = .10) and 25% (HR, 0.75; P = .15) in the BRCA -mutant population.
Grade 3/4 adverse events were more common with the niraparib combination group compared to the placebo group (75% vs 59%), with anemia and hypertension being the most common. However, treatment discontinuations due to adverse remained low (15% with niraparib vs 10% with placebo).
Attard noted, however, that half the target number of patients required for the final analysis died. Still, 'in my view, there's a clear trend for favoring survival in the patients randomized to niraparib,' he told attendees.
'Exciting News' for Patients
The AMPLITUDE results are 'really exciting news for our patients,' McGregor said.
Considering the poor prognosis of patients with metastatic castration-sensitive prostate cancer, 'it is reasonable to prioritize early access to PARP inhibitors for these men, at least for the ones with BRCA mutations,' added ASCO discussant Joaquin Mateo, MD, PhD, with Vall d'Hebron Institute of Oncology, Barcelona, Spain.
However, Mateo explained, 'I think that for patients with mutations in the other genes, I will be more prudent, and I'll be on the lookout for the overall survival data to mature.'
The other key conclusion, Mateo said, is that genomic profiling 'should be moved earlier into the patient course, and I am confident that embedding genomic profiling into the diagnostic evaluations of metastatic prostate cancer is also going to result in better quality of testing, more efficacious testing, and also a more equitable framework of access to testing for patients.'
