Most recently, PARP inhibitors have shown tremendous development in prostate cancer with AKEEGA (Janssen), followed by TALZENNA (Pfizer/Astellas Pharma) and LYNPARZA in combination (AstraZeneca/Merck), all in first line setting received approved in mCRPC in the year 2023.

Janssen’s AKEEGA represents a groundbreaking development as the first and only dual-action tablet that combines a PARP inhibitor, niraparib, with abiraterone acetate and prednisone (AAP). The combination DAT regimen targets two oncogenic drivers in patients with mCRPC, namely alterations in the androgen receptor axis and in BRCA1/2. The drug got FDA approval in August 2023, in the first line setting, for the treatment of patients with mCRPC who have either confirmed or suspected deleterious BRCA-positive mutations. The approval was primarily based on the results of a Phase III MAGNITUDE trial.

Previously, at the primary analysis of MAGNITUDE study, a statistically significant 47% risk reduction was observed for radiographic progression-free survival (rPFS) with niraparib + abiraterone acetate + prednisone in patients with BRCA+ mCRPC.

During the ESMO 2023 conference, the final analysis of the MAGNITUDE study was unveiled. This final analysis focused on formally assessing the secondary endpoints, including overall survival (OS) and time to cytotoxic chemotherapy (TCC), and time to symptomatic progression (TSP). The OS analysis occurred at a median follow-up of 35.9 months (11.1 months of additional follow up from interim analysis 2 and 19.2 months from primary analysis).

A pre-specified multivariable analysis adjusting for baseline imbalances demonstrated a survival benefit favoring the combination of niraparib and AAP. The data revealed a median OS of 30.4 months for patients receiving niraparib + AAP, in contrast to 28.6 months for those who were administered a placebo alongside AAP. Furthermore, a sustained improvement in TSP and TCC were also observed with niraparib + AAP.

Safety remained consistent with the known safety profile of niraparib. Among patients receiving niraparib, abiraterone acetate, and prednisone, 4.7% experienced pulmonary embolism, and there were no instances of myelodysplastic syndrome or acute myeloid leukemia. Transfusion rates were notably higher in the group receiving niraparib, abiraterone acetate, and prednisone at 27.3%, in contrast to 5.2% in the group receiving a placebo alongside abiraterone acetate and prednisone.

The final analysis of MAGNITUDE supports the positive benefit-risk profile of first-line niraparib with abiraterone acetate plus prednisone, establishing the combination as a new standard of care for patients with BRCA+ mCRPC.

KOL insights

“As a physician, identifying patients with a worse prognosis is a priority, especially those whose cancers have a BRCA mutation. These findings from the MAGNITUDE study support establishing niraparib combined with abiraterone acetate as the new gold standard of care for first-line treatment in patients with BRCA-positive mCRPC.” – MD, United States.

Conclusion 

Approximately 10─15% percent of patients with mCRPC have BRCA gene alterations. Patients with BRCA-positive mCRPC are more likely to have aggressive disease and may experience poor outcomes and a shorter survival time. The approval of AKEEGA (niraparib + abiraterone acetate), based on the Phase III MAGNITUDE trial, brings an important treatment option to patients with BRCA+ mCRPC as they consider their road ahead, and it also highlights the importance of genetic testing and precision medicine for this disease. At the primary analysis, the study significantly improved radiographic progression-free survival in BRCA-mutant (BRCA+) patients, with a median rPFS of 19.5 months compared with 10.9 months for placebo as demonstrated in the second interim analysis. 

Results from the final analysis were also favorable. The combination of niraparib and AAP demonstrated a more robust improvement in overall survival (OS) with a median OS of 30.4 months. Beyond OS, other secondary end points assessed in this final analysis, i.e. TSP and TCC also revealed clinically significant enhancements in patients with BRCA-mutant mCRPC.

The extended follow-up did not unveil any novel safety concerns. Adverse events were controllable in both treatment groups, with distinctions primarily attributed to the recognized hematologic side effects linked to niraparib. This positive benefit-risk profile validates AKEEGA as the new benchmark for the management of BRCA+ mCRPC patients.

Janssen’s AKEEGA is likely to compete with Pfizer’s TALZENNA in mCRPC, anticipated to capture a market of USD ~700 million in the United States by 2032.  For more insight into the Prostate cancer types including metastatic CRPC, metastatic CSPC, non-metastatic CRPC and non-metastatic CSPC, their respective geographical patient burden, treatment, and changing market landscape-related advancements, refer to these reports:

• Metastatic Prostate Cancer Market Insight and Forecast
• Metastatic Castration-Sensitive Prostate Cancer (mCSPC) Market Insight and Forecast
• Non-metastatic Prostate Cancer (nmPC) Market Insight and Forecast
• Metastatic Castration-Resistant Prostate Cancer (mCRPC) Market Insight and Forecast