A 37% reduction in the risk of radiographic progression or death was observed with Akeega (niraparib plus abiraterone acetate [Zytiga]) plus prednisone compared with Zytiga, prednisone, and placebo (AAP), in patients with metastatic castration-sensitive prostate cancer (mCSPC) who had homologous recombination repair (HRR) gene alterations and had previously received androgen deprivation therapy (ADT), according to results from the phase 3 AMPLITUDE trial presented at the 2025 ASCO Annual Meeting.
After a median follow-up of 30.8 months, the median radiographic progression-free survival (rPFS) was not estimable in the Akeega group compared with 29.5 months in the placebo arm. Furthermore, Akeega significantly reduced the risk symptomatic progression by 50% compared with AAP and placebo. Overall survival (OS) was not statically significant at the analysis, with trends beginning to emerge showing improvement with Akeega.
“Improvements in rPFS are supported by a statistically significant benefit in time to symptomatic progression and a trend toward improved OS,” lead investigator Dr. Gerhardt Attard, Cancer Institute, University College London, said during a presentation of the findings. “In my opinion, AMPLITUDE supports [Akeega] as a treatment option for patients in this poor prognostic disease group.”
Glossary:
HRR gene alterations: changes in genes like BRCA1 or BRCA2 that affect the cell’s ability to repair DNA damage.
Radiographic progression-free survival (rPFS): time during and after treatment that a patient lives without cancer getting worse on scans.
Overall survival (OS): time from start of treatment until death from any cause.
PARP inhibitor: a type of drug that blocks a protein cancer cells use to repair DNA damage, making them more likely to die.
Androgen deprivation therapy (ADT): treatment that lowers testosterone to slow prostate cancer growth.
De novo M1: metastatic cancer present when the disease is first diagnosed.
High-volume metastatic disease: cancer that has spread widely, often to multiple bones or organs.
Patient Demographics and Additional Findings From AMPLITUDE
In the study, 696 patients were evenly randomized to receive Akeega (348 patients) or placebo plus AAP (348 patients). The median age of enrolled patients was 68 years. Overall, 78% of patients had high-volume metastatic disease (M1), of which 87% were de novo M1. All patients had received ADT for six months or less and 16% of patients had received prior docetaxel. All patients in the study had an alteration in genes associated with HRR, which included BRCA1/2 alterations for 55.6% of patients. Remaining alterations could have been in BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B or RAD54L.
For patients specifically with BRCA mutations, the improvements in rPFS were more pronounced. In this group, there was a 48% reduction in the risk of radiographic progression or death with the addition of the PARP inhibitor. The median for the Akeega arm was not estimable compared with 26 months with AAP.
“This was a really exciting result,” said Attard. “This is the first study to show efficacy for PARP inhibition and androgen receptor inhibition in CSPC, the benefit [of which] might be greatest in patients with BRCA mutations.”
Those with BRCA1/2 mutations also had a significant reduction in the risk of symptomatic progression. In this subgroup, there was a 56% reduction in the risk of symptom progression with the PARP inhibitor compared with the androgen synthesis inhibitor and placebo.
“This is a patient-centric end point, measuring the time to worsening of symptoms, which includes needing radiation or a procedure or intervention or further cancer treatment,” said Attard. “Very convincingly we show a clear benefit with [Akeega].”
OS was still immature across the study. At the analysis, the BRCA1/2 subgroup showed similar trends as in the full population of those with HRR gene alterations. In this group, there was an early 25% reduction in the risk of death observed with Akeega.
“Half the number of patients have died from the target number we would require for the final analysis, but in my view, there’s a clear trend for favoring survival in the patients randomized to [Akeega],” said Attard.
Diving Into the Safety and Possible Implications
Grade 3 (severe) or 4 (life-threatening) adverse effects (AEs; side effects) were observed in 75.2% of those receiving Akeega compared with 58.9% of those in the control arm. The most common AEs were anemia (29.1% with Akeega versus 4.6% with placebo) and hypertension (26.5% versus 18.4%). Of those with anemia, the majority required a transfusion.
Dose interruptions were required for 66.9% of patients in the Akeega arm compared with 42.4% for the control arm. Dose reductions were needed to address AEs for 21.9% of those in the Akeega arm compared with 6.9% of those in the placebo group. Treatment was discontinued for 14.7% of those in the Akeega arm compared with 10.3% of those in the placebo group. Treatment-emergent AEs led to death for 14 patients in the investigational arm compared with seven in the control group.
“We’re used to the side effect profile with these drugs, and we aren’t seeing any new side effects but clearly those randomized to [Akeega] have more AEs than those randomized to placebo,” said Attard. “But critically, I think, the proportion of patients who [were] required to discontinue treatment was fewer than 5% for those on [Akeega] versus placebo.”
In 2023, Akeega was approved by the FDA in combination with AAP for patients with deleterious or suspected deleterious BRCA-mutated castration-resistant prostate cancer, based on findings from the phase 3 MAGNITUDE study. Results from the AMPLITUDE study could expand this approval to those with castration-sensitive disease.
“This is really exciting news for our patients,” ASCO expert commentator Dr. Bradley McGregor, from Dana-Farber Cancer Institute, said of the results. “PARP inhibitors have been a mainstay in the treatment of metastatic castrate-resistant prostate cancer for those patients with HRR alterations, and this is the first time we’ve seen data for these in the hormone-sensitive setting. As you heard this is a very poor prognostic group, so I think this is incredibly exciting.”
Reference:
“Phase 3 AMPLITUDE trial: Akeega for metastatic castration-sensitive prostate cancer with homologous recombination repair gene alterations” by Dr. Gerhardt Attard, et al., Journal of Clinical Oncology.
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