AstraZeneca and Merck & Co.’s Lynparza may have a narrower label than GlaxoSmithKline’s rival drug Zejula in ovarian cancer, but in prostate cancer, the situation could flip.
Adding Lynparza to J&J’s androgen inhibitor Zytiga and a steroid extended the time patients with newly diagnosed metastatic, castration-resistant prostate cancer (mCRPC) could live without disease progression—regardless of their homologous recombination repair (HRR) genetic mutation status.
The Lynparza combination pared down that risk by 34% over Zytiga and steroid alone, according to phase 3 data released at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU). The Lynparza combo added more than eight months to patients’ time to disease progression or death, reaching a median 24.8 months, versus 16.6 months for the control group.
If eventually approved in the broad patient population, Lynparza would have an edge over Zejula, which at the ASCO GU event only reported a benefit on that progression-free survival marker in prostate cancer patients whose tumors harbor HRR mutations.
PARP inhibitors like Lynparza and Zejula have historically worked best in HRR-mutated cancers, most notably those with BRCA mutations. But when paired with Zytiga, “it looks like all bets are off when it comes to the need for selecting patients based on the presence of” HRR defects, Scot Ebbinghaus, M.D., a VP and therapeutic area head for late-stage oncology clinical development at Merck, said in an interview.
AZ and Merck designed the 796-patient phase 3 PROpel trial for all patients independent of HRR status after seeing Lynparza, in combination with Zytiga, worked in previously treated mCRPC, irrespective of HRR biomarker status, in a smaller phase 2 trial. But given PARP inhibitors’ general lack of showing in HRR-negative disease in other cancer types, AZ “knew that one of the questions that was going to be subsequent to that, if you do see a benefit in the [intent-to-treat] population irrespective of biomarker, how do you know that it’s not being carried by the mutant population,” Dave Fredrickson, AZ’s oncology business chief, said in a separate interview.
So the PROpel trial involves predefined subgroup analyses by patients’ HRR status.
There, Lynparza cut the risk of disease progression or death by 50% in patients with HRR mutations as detected by circulating tumor DNA testing, while the magnitude was halved—to 24%—in non-HRR mutation patients. The median time patients lived without progression improved to 24.1 months for the Lynparza takers without mutations, compared with 19 months for the control group. The data showed “essentially consistency” of Lynparza benefit between the two populations, Ebbinghaus said.
But those two numbers lack the rigor of statistical significance thanks to the trial design. About a quarter of patients in the study have HRR aberrations, which roughly reflects the real-world constitution of an estimated 20% to 30% HRR-mutated cases among all mCRPC patients.
Still, Lynparza’s 34% improvement—with the drag from non-HRR-mutated cases—looked better than the 27% that Zejula showed only among HRR-mutated patients in its own phase 3 Magnitude trial, which also paired the drug with Zytiga and steroid therapy.
But it’s worth noting the two trials have important differences. A major one is that Lynparza’s PROpel used investigators’ assessment of progression-free survival, while Zejula’s Magnitude used blinded central review. When it comes to an investigator analysis, Zejula’s benefit rises to 36%; but once again, that’s only for HRR-mutated disease. In patients without a HRR mutation, Zejula offered no additional efficacy on top of Zytiga.
Lynparza also showed a trend toward extending patients’ lives in all comers. But with only 29% of planned death events recorded so far at this interim analysis, the overall survival data are still immature. As Lynparza has pulled off a survival advantage in previously treated mCRPC patients with BRCA1/2 or ATM gene mutations in the phase 3 PROfound trial, Fredrickson said he’s confident that the drug would eventually show a survival benefit in the first-line setting as well.
Zejula, developed by Tesaro and now its new owner GlaxoSmithKline, celebrated an FDA nod in 2020 as a so-called first-line maintenance treatment for women with platinum-responsive ovarian cancer regardless of their biomarker status. Lynparza monotherapy’s later FDA go-ahead is limited to BRCA-mutated disease, and its use in a broader ovarian cancer population with homologous recombination deficiency requires combination with Roche’s Avastin.
Nevertheless, Lynparza has maintained a market leadership with $2.75 billion in 2021 sales for AZ after 21% year-over-year growth, thanks in part to its additional indications in breast cancer, pancreatic cancer and previously treated mCRPC, all of which are limited to either BRCA or HRR mutations. By comparison, Zejula only reeled in £395 million ($534 million), with a similar 22% increase over 2020.
With its FDA nod in second-line mCRPC in 2020, Lynparza became the first molecularly-driven therapy in the disease that requires biomarker testing. But the COVID-19 pandemic has been “a difficult context to create new testing behavior within,” Fredrickson said. So far, AZ has managed to push the U.S. HRR testing rate in prostate cancer close to about 50%, he added.
Now, Lynparza looks on track to gain another strong foothold in prostate cancer, possibly for a wider population. Zejula, owned by J&J in prostate cancer, may be limited in the HRR mutation circle, where it’ll have to fight hard with Lynparza for share.
At least AZ is still interested in driving HRR testing in prostate cancer. “It’s always important to understand the biomarker so as we tailor therapy in the second line if they don’t see Lynparza in the frontline that there’s an opportunity to do that in the later-line setting, consistent with PROfound,” Fredrickson said.