In 2017 and 2020, Zejula snagged broad FDA labels for ovarian cancer patients who responded well to a chemotherapy. But in prostate cancer, the PARP inhibitor appears to work only for a niche population—and that's bad news for the drug in its ongoing fight for market supremacy against AstraZeneca and Merck & Co.’s rival Lynparza.
In a late-stage clinical trial in patients with newly diagnosed metastatic, castration-resistant prostate cancer (mCRPC), the addition of Zejula to J&J’s Zytiga and prednisone slashed the risk of disease progression or death by 27% in patients with mutations in their homologous recombination repair (HRR) genes. The phase 3 data were unveiled at the American Society of Clinical Oncology Genitourinary Cancers (ASCO GU) symposium.
But in patients without HRR abnormalities, Zejula didn’t show any efficacy benefit but instead added toxicity to the Zytiga-prednisone regimen. That part of the readout came in stark contrast to Lynparza’s win at ASCO GU in all patients in the same disease setting regardless of HRR status.
By grouping patients into different cohorts by HRR status, J&J intentionally designed the phase 3 MAGNITUDE trial to examine which patients really benefit from the new Zejula combination, Mark Wildgust, Ph.D., vice president of global medical affairs at J&J’s Janssen, said during an interview. And the trial was successful in that it tells the scientific community that Zejula works best in HRR-mutant disease in mCRPC, he added. A prospective analysis like this one is often considered scientifically more rigorous than a post-hoc assessment.
“Our study provides physicians the confidence and the clarity on who to use [Zejula] in,” Wildgust said. In mCRPC, an estimated 20% to 30% of patients have HRR mutations.
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PARP inhibitors such as Zejula and Lynparza are known to work best in cancers with HRR alterations, especially BRCA1/2 mutations. For example, Lynparza’s most recent U.S. expansion in previously treated metastatic, castration-resistant prostate cancer is confined to HRR-mutated cases. Meanwhile, homologous recombination deficiency (HRD) is the requirement for Lynparza’s use in ovarian cancer patients who responded to an initial round of chemo in the so-called first-line maintenance setting.
For its part, Zejula had previously won FDA approvals as maintenance treatment for women with newly diagnosed and recurrent ovarian cancer beyond HRR deficiencies under developer Tesaro and its new owner GlaxoSmithKline. J&J in-licensed Zejula’s prostate cancer rights through a 2016 deal with Tesaro.
The tables were turned this time. While Zejula failed in first-line mCRPC patients without HRR, Lynparza, used on top of Zytiga and steroids, cut the risk of disease progression or death in all patients by 34% regardless of HRR status in its own phase3 PROpel trial. A predefined subgroup analysis showed an improvement of 46% for the HRR-mutated group, according to data published at ASCO GU.
Cross-trial comparisons have various problems. Zejula’s 27% number came from a blinded central review, while Lynparza’s 46% result was drawn by investigators. When evaluated by investigators, Zejula’s benefit in HRR-mutated patients widened to 36%.
The two trials also included slightly different patient populations. While Lynparza’s PROpel excluded patients with any prior Zytiga exposure, Zejula’s MAGNITUDE allowed those patients as long as they had received the CYP17 inhibitor within four months before randomization. As Wildgust described it, MAGNITUDE enrolled a population matching the patients seen in clinical practice today.
Wildgust also pointed to imbalances in certain patient baseline characteristics that may have hurt Zejula’s showing. The Zejula patients are less healthy as measured by the ECOG score compared with the control group and had higher number of visceral metastases, both of which are associated with poorer outcomes, he noted.
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Still, those detailed differences will be hard to convey to physicians. If approved, Zejula’s failure in the HRR non-mutated population could be a major obstacle for overall uptake as getting the drug may require a test for HRR status. If it were any consolation, in ovarian cancer, Lynparza has been able to maintain its lead in HRD-positive share as Zejula conquers the HRD-negative group. But that’s based on Lynparza’s existing market dominance.
J&J might be able to leverage its existing position in prostate cancer; after all, J&J developed now-off-patent Zytiga, and the company also sells growing androgen receptor inhibitor Erleada.
Besides Lynparza and Zejula, Pfizer is pairing its PARP inhibitor Talzenna with Astellas-partnered androgen receptor antagonist Xtandi in mCRPC in the TALAPRO-2 trial, which bears a primary completion date in March. Talzenna is currently only approved in BRCA-mutated breast cancer.
J&J is also focusing its prostate cancer R&D on a new target called KLK2, Wildgust said. That work includes three different drugs: JNJ-75229414, a KLK2-targertd CAR-T therapy; JNJ-78278343, a KLK2 x CD3 T-cell-redirecting bispecific antibody; and JNJ-69086420, a radiotherapy-antibody drug conjugate.
Editor's Note: The story has been updated to further clarify J&J's perspective that the trial was designed to understand which patients would best benefit from Zejula, and it was successful in doing that.