PARP inhibitors making inroads towards the first line metastatic Castrate-resistant prostate cancer (CRPC) market soon?

Delveinsight brings you the comparative analysis on Positive Phase III trial results of PARP inhibitors, Zejula (Niraparib) and Lynparza (Olaparib) in metastatic CRPC patient population.

PARP inhibitors are one of the most promising therapeutic classes in the phase III pipeline, based on the demonstrated effectiveness of Olaparib (Lynparza; AstraZeneca) and Rucaparib (Rubraca; Clovis Oncology) in Prostate Cancer. Two PARP inhibitors, Rucaparib, and Olaparib have already received FDA approval in May 2020 for use in mCRPC in later line settings, however we still await to see the approval of PARP inhibitors in the first line setting of mCRPC. AstraZeneca and Merck are GlaxoSmithKline/Johnson & Johnson’s main competitors in this field as of now, especially in the first-line setting. They also reported Phase III PROpel trial data at ASCO GU 2022, and we believe that Olaparib has the potential to be the first-ever PARP inhibitor in first-line mCRPC.

• Positive results of Phase III MAGNITUDE study of Zejula (Niraparib) in combination with Zytiga (Abiraterone Acetate) in mCRPC patients with and without HRR gene alterations (Abstract #12)

At the ASCO GU 2022, Johnson & Johnson (J&J) announced the results from its pivotal Phase III MAGNITUDE (NCT03748641) study for Niraparib in patients with homologous recombination repair (HRR) gene-altered mCRPC. According to the results presented, niraparib plus Abirateroneresulted in a 47% improvement in rPFS (Radiographic Progression-Free Survival) in patients with BRCA 1/2 alterations and a 27% improvement in all HRR biomarker positive patients after a median follow-up of 18.6 months. The median rPFS was 16.6 months with niraparib plus Abirateronein BRCA 1/2 population while in patients with HRR gene alterations it was 16.5 months. The combination improves rPFS and other endpoints in patients with HRR related genes, but there is no sign of benefit in people who do not have HRR biomarkers. The safety profile of niraparib with abiraterone acetate/prednisone was manageable, with no new safety signals found, and health-related quality of life was maintained.

“MAGNITUDE highlights the importance of testing for HRR gene alterations in patients with mCRPC, to identify who will optimally benefit from the combination of niraparib plus abiraterone” – Expert opinion

Analyst Opinion: As patients with DNA repair mutations typically have the worst prognosis and have a poor response to NAA, first-line treatment options should be available that not only improvises the outcomes but are innovative as well.  The first-ever results of the GSK and J&J’s Phase III MAGNITUDE study of Niraparib show that niraparib in combination with abiraterone acetate/prednisone could be the new first-line treatment for those men with mCRPC with HRR gene mutation. Based on the existing scenario, one can conclude that AstraZeneca/Merck & Co’s Olaparib has an advantage over GSK/J&J Niraparib in terms of target patient pool. Olaparib has a significantly larger pool than Niraparib.  In addition to Olaparib and Niraparib, Talazoparib (Talzenna, Pfizer) and Rucaparib (Rubraca; Clovis Oncology) are also being studied in first-line mCRPC trials as well, Talapro-2 (NCT03395197; Active, not recruiting) and Caspar (NCT04455750; Recruiting), respectively.

• Longest radiographic PFS of Lynparza (olaparib) with Zytiga (abiraterone acetate) achieved in Phase III PROpel study in first-line mCRPC  (Abstract #11)

Outcomes from the PROpel Phase III study (NCT03732820) showed player AstraZeneca and Merck’s Lynparza demonstrated strong efficacy as first-line treatment in men with mCRPC. The data showed that the median investigator-assessed rPFS was 24.8 months which is statistically significant and clinically meaningful. The study also indicates a positive trend toward better overall survival (OS), although the difference did not achieve statistical significance at the time of the data cut-off (analysis at 29% data maturity). The study will continue to evaluate OS as a key secondary endpoint. Furthermore, the one-year and two-year rPFS rates were 71.8% and 51.4%, respectively. When the medicine was examined using a blinded independent central review, the median rPFS was 27.6 months, resulting in a 39% reduction in the probability of rPFSor death. PROpel met its primary endpoint which demonstrated a significant improvement in rPFS for Lynparza plus Zytiga in mCRPC patients irrespective of the HRR status.

“This benefit led to what I think is the longest rPFS we have seen to date in metastatic CRPC beyond 2 years” – Expert opinion

Analyst Opinion:

Lynparza has achieved front-line success in the Phase III Propel study. The main distinction between Lynparza and Zejula is that Lynparza’s benefit appears to be independent of patients’ HRR status, whereas Zejula’s benefit appears to be limited to HRR-mutated. Another Advantage of Lynparza is that there will be no need for genetic testing because this first-line treatment is for mCRPC people irrespective of biomarker status. As a result, the company may have leverage over Zejula, which has demonstrated promising outcomes in HRR-positive mCRPC patients, and where the need for genetic testing to select target pool becomes crucial. Owing to this benefit, AstraZeneca and Merck’s Lynparza may be able to reach a large number of mCRPC patients. The investigators of this study also highlighted that the rPFS shown with olaparib is the longest rPFS seen in mCRPC to date, i.e., roughly 25 months. In conclusion, the PROpel Phase III study findings are statistically significant and clinically important as first-line therapy for individuals with mCRPC who have HRR gene mutations or not.