At the American Society of Clinical Oncology (ASCO) Annual Meeting 2025, held from 31 May to 3 June in Chicago, Illinois, updated efficacy and safety data from the randomised, double-blind, placebo-controlled Phase III AMPLITUDE (NCT04497844) clinical trial were presented on 3 June. This trial evaluated the efficacy and safety of Johnson & Johnson’s (J&J) Akeega, which includes Zejula (niraparib), a highly selective poly (ADP-ribose) polymerase (PARP) inhibitor marketed by GSK for other indications, and Zytiga (abiraterone), a CYP17 inhibitor, plus the corticosteroid prednisone, in treating patients with deleterious germline or somatic homologous recombination repair (HRR) gene-altered metastatic castration-sensitive prostate cancer (mCSPC), a condition in which the cancer has spread to other parts of the body but still responds to androgen deprivation therapy (ADT).
Prostate cancer (PC) is the second most common cancer among men globally, following lung cancer, and patients with CSPC represent an area of unmet need in terms of available treatment options. According to GlobalData’s Prostate Cancer: Epidemiology Forecast to 2033 report, the number of diagnosed five-year prevalent cases of PC in the eight major markets (8MM: China, France, Germany, Italy, Japan, Spain, the UK and the US) is projected to increase from 3,517,086 in 2025 to 4,236,251 by 2033.
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In the AMPLITUDE trial, a total of 696 patients with HRR gene-altered mCSPC were randomised 1:1 to experimental arm A (Akeega + prednisone; n=348) and comparator arm B (placebo + prednisone; n=348). The study achieved its primary endpoint of radiographic progression-free survival (rPFS). For patients with breast cancer (BRCA, or BRCA1 and BRCA2 ) gene mutations, a subset of HRR mutations, in arm A (n=191), median rPFS was not reached, compared to 26 months for arm B. This corresponded to a 48% reduction in the risk of progression or death (hazard ratio [HR] 0.52; 95% confidence interval [CI], 0.37 to 0.72; p<0.0001).
Among patients with any HRR alteration in arm A, median rPFS was also not reached with the niraparib combination versus 29.5 months in arm B, reflecting a 37% reduction in risk (HR 0.63; 95% CI, 0.49 to 0.80; p=0.0001). The niraparib combination reduced the risk of symptomatic progression by 56% in BRCA-altered patients (HR 0.44; 95% CI, 0.29–0.68; p=0.0001) and by 50% in those with HRR alterations (HR 0.50; 95% CI, 0.36–0.69; p<0.0001), delaying symptom worsening and the need for additional interventions.
First-generation PARP inhibitors have been linked to higher toxicity
The first interim analysis showed an early, but not statistically significant, trend toward improved overall survival (OS) favouring arm A, with a 25% reduction in the risk of death in patients with BRCA alterations (HR 0.75; 95% CI, 0.51–1.11; p=0.15) and a 21% reduction in those with HRR alterations (HR 0.79; 95% CI, 0.59–1.04; p=0.10). Follow-up is ongoing to reach data maturity. Grade 3 and 4 adverse events occurred more often in arm A than in arm B (75% versus 59%). This trial concludes that the combination of Akeega plus prednisone is a treatment option for patients with HRR-altered mCSPC, especially those with BRCA mutations.
In 2023, the FDA approved Akeega in combination with prednisone for patients with BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC), based on the results of the MAGNITUDE trial. Currently, ADT and androgen receptor pathway inhibitors (ARPIs) remain the only treatment options for patients with mCSPC, with no PARP inhibitor therapies approved in this setting until now. The AMPLITUDE study results mark a significant milestone, positioning Johnson & Johnson’s combination of a PARP inhibitor with ADT as the first targeted therapy for patients with BRCA-mutated mCSPC.
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By GlobalDataHowever, the efficacy appears heterogeneous in the non-BRCA subgroup. A more detailed analysis is needed for this group, which makes up approximately 45% of the AMPLITUDE study population. Pfizer’s Talzenna (talazoparib), in combination with Xtandi (enzalutamide), is currently being evaluated in the ongoing Phase III TALAPRO-3 trial for patients with DNA damage response-deficient mCSPC. AstraZeneca’s next-generation, first-in-class PARP1 inhibitor, saruparib, is being assessed for efficacy and safety in HRR-mutated mCSPC patients in the Phase III EvoPAR-PR01 trial, in combination with either ADT or ARPI. First-generation PARP inhibitors are associated with higher toxicity, including bone marrow suppression and the risk of myelodysplastic syndrome. If saruparib demonstrates superior OS and a more favorable toxicity profile in the EvoPAR-PR01 trial, it may become the preferred option for clinicians over Akeega plus prednisone in HRR-mutated mCSPC.
However, the estimated completion date for this trial is 2031, meaning that competition to Akeega could emerge in the later 2020s. According to GlobalData’s analyst consensus forecast, global sales for Akeega are projected to reach $676 million by 2030, while Talzenna and saruparib are expected to reach $618 million and $628 million, respectively, in the same year.
