Positive results from the Phase III PrOpel study, investigating the combination of Lynparza (olaparib) with abiraterone as a first-line option for patients with metastatic castration-resistant prostate cancer (mCRPC), may further set Lynparza apart as the poly (ADP-ribose) polymerase inhibitor (PARPi) of choice.

AstraZeneca/Merck presented their key findings at the 2022 annual American Society of Clinical Oncology-Genitourinary Cancer Symposium (ASCO-GU) meeting on 17–19 February, which revealed a significantly improved radiographic progression-free survival (rPFS) of 24.8 months, versus the 16.6 months of the placebo and abiraterone arm. More importantly, the results demonstrated a benefit in patients, irrespective of the homologous recombination repair (HRR) status, thus conferring an advantage over other PARPis by averting testing hurdles typically observed in lower-budgeted hospitals. Competition for Lynparza’s number one spot is expected from Janssen Biotech’s Zejula (niraparib), whose abiraterone-prednisolone combination revealed a 47% improvement in the rPFS of BRCA 1/2 mutant patients, and 27% across all HRR biomarker-positive patients. However, the competitive impact of Zejula will be limited by its dependency on patients with an HRR gene alteration.

Since PARP inhibitors differ in their pharmacokinetics and pharmacodynamics, Pfizer’s Talzenna (talazoparib) combined with Astella’s androgen receptor antagonist Xtandi (enzalutamide), if approved, may extend the pressure on Lynparza. A readout of the TALAPRO-2 (NCT03395197) study, bearing a primary completion date of March 2022, is expected this year, with Pfizer hoping for a significantly improved rPFS in both its molecularly unselected, and DNA damage response-deficient mCRPC patients. 

In the absence of generics, the unequivocal winner of the Lynparza–Zejula battle would have been Johnson & Johnson’s Zytiga (abiraterone). However, the post-2018 influx of generic competitors has drastically eroded the originator, with Zytiga representing just 13.7% of the total abiraterone units sold in December 2020. Nevertheless, despite generic erosion and competition from newer therapies, Zytiga brought in $2.3 billion worldwide in 2021. A PROpel, or MAGNITUDE-backed, indication should indirectly reduce the rate of Zytiga sales erosion by increasing its patient pool with PARPi combinations.

Of the four PARP inhibitors in the race for the first-line indication, Rubraca is the furthest behind, with its Xtandi (enzalutamide) combination study still at Phase Ib, unlike the Phase III positioning of the other PARP inhibitors. Thus, Rubraca, which already has an FDA indication for second-line mCRPC patients, is set to experience a significant decline in shares, should its competitors gain approval. Rubraca’s market share will be intimately tied to the number of PARPi-naïve patients available post-first-line. Lynparza’s European Medicines Agency (EMA) and FDA approval for second-line mCRPC patients in 2020 gives the PARPi an edge over Zejula and Talzenna, regarding physician familiarity. Together with the results of PrOPel, it lends additional momentum to AstraZeneca and Merck’s Lynparza expansion bid. In 2021, Lynparza pulled in $2.3 billion in product sales worldwide across its ovarian, breast, pancreatic, and prostate cancer indications. An FDA nod for a first-line indication will further drive Lynparza’s sales.