Background introduction

On October 21, 2024, Johnson & Johnson announced that its dual-effect combination tablet, Akeega(Niraparib and Abiraterone Acetate) had been officially approved for marketing by National Medical Products Administration (NMPA) for use in combination with prednisone or prednisolone in the treatment of metastatic castration-resistant adult prostate cancer patients (mCRPC) with germline and/or somatic BRCA mutations. This is the first and only approved double-effect compound preparation in China. This combination was approved by the US FDA in August 2023 for the treatment of patients with BRCA mutation mCRPC and may be used in combination with prednisone or prednisolone.

01.BRCA mutant prostate cancer

Prostate cancer is the largest cancer in urinary system. Although the incidence of prostate cancer in China is much lower than that in Europe and America, it has been increasing year by year in recent years. In China, the majority of newly diagnosed cases of prostate cancer are in the advanced clinical stage, and the clinical limited cases are only 30%, which leads to the poor overall prognosis of patients with prostate cancer in China. From 2003 to 2015, the age-standardized 5-year survival rate of prostate cancer in China increased from 53.8% to 66.4%, but compared with the overall 5-year survival rate of male prostate cancer in developed countries, there is still a large gap ^[1].

The mutation frequencies of HRR-related genes in prostate cancer were (5.3%–13.0%). An integrated analysis of the whole exon and whole transcriptome data in patients with metastatic castration-resistant prostate cancer (mCRPC) found that 12.7% of patients had BRCA1/2 biallelic inactivation, and up to 19.3% of patients had HRR-related gene mutations ^[2].

mCRPC is the terminal stage of the disease development of prostate cancer and has mutations in multiple signaling pathways, so the disease has high heterogeneity and poor overall prognosis. Patients with MCRPCs with BRCA1/2 gene mutation have poor prognosis. Compared with patients without mutation, patients with MCRPCs with BRCA1/2 gene mutation have mrPFS of only 7.1 months and mOS of 19.4 months 1 after receiving the existing first-line standard treatment. Therefore, effective treatment is urgently needed to improve the survival benefits of these patients ^[3].

The results of the PROfound study showed that olapari reduced the risk of disease progression or death by 66% in patients with mCRPC harboring pathogenic or possibly pathogenic mutations of BRCA and ATM. The independent review committee assessed that PFS could be improved in patients harboring pathogenic or possibly pathogenic mutations of other HRR genes, including BRCA, ATM, BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, RAD51B/C/D and RAD54L ^[4].

02. Basis of approval

This approval was based on a randomized, double-blind, placebo-controlled, multicenter, Phase III MAGNITUDE study. This study was designed to evaluate the efficacy and safety of niRapali/abiraterone plus prednisone in patients with either positive (HRR+, n=423) or negative (HRR, n=247) HRR genes. The primary endpoint was rPFS, and secondary and additional endpoints included OS, and others. The results showed a significantly reduced 45% risk of radiographic progression in patients with BRCA1/2 mutations compared with Placebo in combination with Abiraterone, mrPFS of 19.5 months vs 10.9 months (HR 0.55, 95% Cl 0.39-0.78, P = 0.0007). Final OS analysis showed a 21% reduced risk of all-cause death (mOS：30.4 months vs 20.8 months) with a median follow-up of 35.9 months for Niraparib / Abiraterone compared with Abiraterone. Niraparib / Abiraterone has been shown to work better in patients with BRCA1/2 mutant castration-resistant prostate cancer (mCRPC) than Placebo plus Abiraterone.

Niraparib / Abiraterone vs Placebo + Abiraterone rPFS^[5]

A similar benefit trend was observed in the subgroup analysis of Asian populations published by ESMO Asia in 2023. The Niraparib / Abiraterone group significantly reduced the risk of radiographic progression by 71% in patients with BRCA1/2 mutations compared with the placebo-plus Abiraterone group, with mrPFS of 22.0 months vs 8.3 months (HR 0.29, p=0.0084).

03.FDA approval information

Multiple large Phase II clinical studies, including TOPARP-A, TRITON2, and TOPARP-B, have shown that patients with somatic or embryogenic variant mCRPC with DNA repair (in particular, BRCA1/2) may be susceptible to PARP inhibitors. Phase III clinical study PROfound has clearly confirmed that patients with HRR gene mutation (especially BRCA1/2 and ATM) can benefit from olaparib monotherapy, and patients with BRCA1/2 and ATM mutation have a 66% reduction in the risk of imaging progression or death ^[6].

Based on the three studies of TALAPRO-2, PROpel, and MAGNITUDE, the FDA has successively approved the application of Talazoparib+Enzalutamide, Olaparib+Abiraterone +Prednisone/Prednisolone, and Niraparib+Abiraterone acetate+Prednisone or Prednisolone in mCRPC.

04. Combined treatment

Akeega (Niraparib and Abiraterone Acetate) is the first domestic approved regimen of PARP inhibitors combined with new endocrine drugs for the first-line treatment of mCRPC with BRCA1/2 gene mutation. This innovative therapy significantly prolonged our patient's progression-free survival and demonstrated significant efficacy in the Asian population. A number of authoritative guidelines both in China and abroad, including CSCO, have recommended the use of niRapali in combination with abiraterone as a treatment option for patients with mCRPC with BRCA1/2 gene mutation.

Akeega is expected to become the new first-line treatment standard for this patient group and further improve the prognosis and quality of life of patients with advanced prostate cancer.

05. SpaceGen gene detection

SpaceGen involved in the field of tumor gene detection. It has special detection products for various urinary system tumors, including prostate cancer, which can provide patients with important evidence in key aspects such as treatment decision-making and genetic screening, helping doctors and patients to choose more effective treatment strategies.

Pan Solid Tumor Sequencing Panel Assay (175 genes)

● Targeted related genes

● MSI predicts immune efficacy

● Prediction of therapeutic effects of immunotherapy with positive and negative immune correlation factors

● Efficacy prediction of common chemotherapeutic drugs

● Genetic tumor risk assessment

Include 175 core genes for tumor diagnosis and treatment

Applicable population

● Evaluation of adjuvant targeted drugs after operation

● First-line medication evaluation of newly diagnosed first-time patients

● Patients with targeted drug resistance seeking new treatment options

● Patients unable to provide tumor tissue samples

● Patients in need of efficacy evaluation of immunotherapy

Sample type

● Tissue sample (for genetic tumor gene detection, blood control is required)

● Blood sample

Detection Advantage

● Accurate interpretation of targeted drugs

● The therapeutic effect of immunotherapy can be interpreted (positive and negative genes related to immunologic efficacy, MSI)

● Interpretation of common chemotherapeutic drugs (26 chemotherapy-related genes +MSI)

● Genetic tumor risk assessment

● Probe method is adopted for detection, and UMI is added for de-weighting, so as to improve the detection sensitivity

References

[1] Guidelines for prostate cancer screening, early diagnosis and early treatment in China (2022, Beijing)

[2] Expert consensus on clinical detection and application of defects repaired by homologous recombination (2021 edition)

[3] Olmos D, et al. Ann Oncol. 2024; 35(5):458-472.

[4] Target Oncol. 2021 Sep; 16(5):613-623.

[5] Eur J Cancer 2024 Sep:209:114183.

[6] China prostate cancer patients gene detection expert consensus (2020 edition)

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