Just days after Clovis Oncology Inc.'s Rubraca (rucaparib) became the first PARP inhibitor approved by the FDA to treat certain cases of metastatic prostate cancer (mCPRC) in third-line care, the agency granted an even broader label in the indication to its first-in-class competitor, Lynparza (olaparib). Endorsement of second-line use of Lynparza in mCPRC and an overall survival (OS) benefit listed in its updated label will help rapidly establish it as "the drug of choice in the [second] line, leaving little commercial opportunities for Rubraca downstream," SVB Leerink analyst Andrew Berens said.
Alongside Lynparza's label expansion, Foundation Medicine Inc.'s Foundationone CDx and Myriad Genetics Inc.'s BRACAnalysis CDx gained approvals to identify patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated disease for treatment with the drug.
Despite the potentially changed dynamic, neither shares in Clovis (NASDAQ:CLVS) nor Lynparza collaborators Astrazeneca plc (NYSE:AZN) and Merck & Co. Inc. (NYSE:MRK) moved much Wednesday, perhaps because ovarian cancer – the first indication for both drugs – remains a bigger revenue driver. With Wednesday's approval, Lynparza is now approved in seven different indications across four different tumor types.
Both the drug and diagnostic approvals turned on results from the phase III Profound trial, an open-label study in which twice-daily dosing of Lynparza was compared to an investigator’s choice of either Xtandi (enzalutamide, Pfizer Inc. and Astellas Pharma Inc.) or Zytiga (abiraterone, Johnson & Johnson).
On the trial's primary endpoint of radiological progression-free survival, Lynparza yielded a statistically significant improvement vs. investigator’s choice among men with mCRPC selected for BRCA1/2 or ATM gene mutations, with a median of 7.4 months vs. 3.6 months in the investigator’s choice group (HR 0.34; 95% CI: 0.25, 0.47; p<0.0001).
Additional results, announced in April, also showed a statistically significant improvement in the key secondary endpoint of overall survival. Results showed Lynparza reduced the risk of death by 31% (HR 0.69 [95% CI, 0.50-0.97], p=0.0175) and improved OS to a median of 19.1 months vs. 14.7 months for those treated with enzalutamide or abiraterone.
That's important because "clinical benefit is what clinicians and patients are really looking to see," Mark Sims, head of Astrazeneca's U.S. DNA damage response franchise, told BioWorld. "Lynparza is really the only PARP inhibitor that has demonstrated that kind of benefit in a phase III comparative trial," he said, adding that, while it's a positive thing for prostate cancer patients to have more therapeutic options approved, when compared to Rubraca, "it's really just apples and oranges when it comes to the clinical evidence."
Prostate cancer is the second-most common cancer in men and, despite an increase in the number of available therapies for men with mCRPC, five-year survival remains low, below 30%. HRR gene mutations occur in about 20% to 30% of patients with mCRPC.
The OS data, included in the label, proved to be a "best case scenario," Berens told clients in a Wednesday morning note on the news. "We were unsure that the OS benefit would be included in the initial label given the proximity of the data readout to the action date," Beren's SVB Leerink team said. "Based on this better-than-expected label, we have increased our worldwide Lynparza mCRPC revenues to about $1.15 billion at peak from about $1 billion to reflect increased market share and greater penetration into the HRR/HRD+ subtypes," they added.
The Profound study also included tests of both of the companion diagnostics that can be used in support of Lynparza's new indication, Myriad's BRACAnalysis CDx, which supports blood and saliva testing to identify patients with BRCA1 and BRCA2 gene mutations, and Foundation's Foundationone CDx, which is a tissue-based test that identifies patients with HRR gene alterations in prostate tumor tissue. Adding the latter is a boon for Astrazeneca and Merck, as the ability to identify and treat patients with HRR mutations "allows us to reach and benefit a much bigger group of patients," Sims said.
Brian Alexander, Foundation Medicine's chief medical officer, said the combined approval "underscores the value of comprehensive genomic profiling in advanced cancer patients as it validates our ability to identify alterations in the 14 HRR pathway genes" within the diagnostic's panel.
While hormonal agents remain the cornerstone class of drug treatment across all prostate cancer populations, by 2028, PARP inhibitors are predicted to be the second sales-leading class in mCPRC, according to Decision Resources Group (DRG). Including the most recent approvals and expected approvals of combination with hormonal agents in mCPRC, PARP inhibitors could capture combined sales of $2.5 billion across major markets by 2028, DRG analysts predict. (DRG, like BioWorld, is part of Clarivate plc.)
Toward a potential future combination approach in mCRPC, Astrazeneca and Merck are exploring additional trials in metastatic prostate cancer, including the ongoing phase III Propel trial evaluating Lynparza as a first-line therapy in combination with Zytiga for patients with mCRPC vs. Zytiga alone.
Not to be left out, Clovis is also working to expand Rubraca’s remit through testing for the treatment of mCRPC patients in the Triton2 trial for patients with BRCA mutations and is also enrolling patients with deleterious mutations of other HR repair genes, including ATM. It’s also running the Triton3 trial for patients with BRCA mutations and ATM mutations who have progressed on androgen receptor-targeted therapy and who have not yet received chemo in the castrate-resistant setting. Both trials are open for enrollment, according to the company’s website.