Lynparza under siege in first-line prostate cancer

prostate cancer blue ribbon
Marijana via Pixabay

Battle lines are being drawn up in metastatic castration-resistant prostate cancer (mCRPC), with AstraZeneca and Merck & Co’s market-leading PARP inhibitor Lynparza firmly in the sights of newer rivals.

New data on Lynparza (olaparib), as well as PARP drugs from Pfizer and Johnson & Johnson, were presented this week at the 2023 ASCO Genitourinary Cancers Symposium (ASCO GU) in previously-untreated patients with mCRPC, which represents a big new market for the drugs.

Currently holding the higher ground is Lynparza, which was approved for mCRPC associated with homologous recombination repair (HRR) mutations in 2020 and which got a green light in the EU last December for a broader, all-comer population based on interim results of the PROpel trial.

The FDA is also reviewing the data and due to deliver a verdict soon, after delaying its decision by three months.

At ASCO GU, AZ and Merck reported final overall survival (OS) results from PROpel, showing that Lynparza in combination with anti-androgen therapy Zytiga (abiraterone) and prednisone or prednisolone was associated with a median OS of 42.1 months, compared to 34.7 months with abiraterone plus placebo.

That 7.4 month difference did not, however, achieve statistical significance, despite a significant 34% reduction seen with AZ and Merck’s drug on radiographic progression-free survival (rPFS), which formed the basis of regulatory filings. The biggest benefit on rPFS was seen in patients with BRCA mutations, as would be expected given the drug’s mechanism.

Despite the miss, AZ and Merck insisted the data reinforced the profile of Lynparza as an add-on to first-line hormonal therapy for mCRPC, which analysts have suggested could be a blockbuster market for PARP drugs.

Against that backdrop, two potential challengers have emerged in the first-line, all-comer setting. Pfizer reported new data at ASCO GU from the TALAPRO-2 study of its PARP drug Talzenna (talazoparib) in combination with its Astellas-partnered androgen inhibitor Xtandi (enzalutamide) as a first-line therapy for mCRPC on top of hormonal therapy.

The results revealed a 37% improvement in rPFS at a mid-study analysis compared to placebo plus Xtandi, as well as a trend to improved overall survival, so far roughly mirroring Lynparza. Talzenna has also been filed for approval based on the interim data, with a decision due later this year, and has previously been cleared for BRCA-mutated breast cancer. 

J&J, meanwhile, announced updated results from the MAGNITUDE study of niraparib plus Zytiga and prednisone, which revealed a 45% improvement in rPFS among patients with BRCA mutations at a second interim update, plus a trend towards improved OS.

So far, there is no significant effect of the drug on patients without HRR mutations, so close attention will be paid to that data as it matures, along with results from a cohort of patients treated with a fixed-dose combination of niraparib plus abiraterone. In the meantime, J&J and the investigators are pointing to the results as evidence that genomic testing of mCRPC patients remains critical. 

J&J acquired rights to niraparib in prostate cancer from Tesaro in 2016, ahead of the company’s acquisition by GSK in 2019. The PARP is already sold by GSK as Zejula to treat ovarian, fallopian tube, and peritoneal cancers.

For now, it’s not clear whether the newer drugs will pose a serious challenge to Lynparza, although Talzenna seems to be the biggest threat – particularly if it can translate its OS trend to a significant difference at the final analysis.

In Lynparza’s favour is that it is already used in a broad range of indications across ovarian, breast, fallopian tube, peritoneal, and pancreatic cancers. The drug has become AZ’s third-biggest drug, with sales rising 6% to almost $2.6 billion last year.