ESMO: AstraZeneca, Merck tout Lynparza's 'clinically meaningful' ovarian cancer survival edge but lose one in prostate cancer

In a heated PARP inhibitor race with GSK, AstraZeneca and Merck hope some new survival data could consolidate Lynparza’s lead in an ovarian cancer subset. But Merck can’t say the same about a potential prostate cancer expansion.

The combination of Lynparza and Avastin cut the risk of death by 38% compared with Avastin alone in ovarian cancer patients bearing tumors with a biomarker known as homologous recombination deficiency (HRD). The patients received the combo in the first-line maintenance setting after responding to a round of chemotherapy.

An estimated 65.5% of Lynparza-Avastin takers are expected to be alive at five years, versus 48.4% for solo Avastin, according to investigators’ analysis of the phase 3 PAOLA-1 trial. The data will be presented at the European Society for Medical Oncology congress 2022.  

Although the patient survival benefit wasn’t statistically significant because of the trial design, “the good news here is that the treatment effect really persists very nicely,” Scot Ebbinghaus, M.D., vice president of clinical research at Merck Research Labs said in an interview ahead of the data presentation.

Previously, the Lynparza-Avastin combo got FDA approval in HRD-positive ovarian cancer after showing it could slow disease progression or death.

As expected, the drug’s benefit was more pronounced in patients with BRCA-mutated tumors, with a death risk reduction of 40%. In those with other HRD types, the reduction was 29%. Again, Lynparza didn’t confer any survival benefit to patients without HRD; instead, in that patient subgroup, those on placebo appeared to have lived even longer.

Separately at this year's ESMO, Lynparza monotherapy showed that as a first-line maintenance therapy, it could reduce the risk of death by 45% over placebo in BRCA-mutated patients with BRCA-mutated ovarian cancer who responded to induction chemotherapy, according to an update of the SOLO-1 trial.

Investigators of PAOLA-1 and SOLO-1 called Lynparza’s survival benefits “clinically meaningful,” though neither trial showed statistically significant results.

“Achieving long-term survival for patients with newly diagnosed advanced ovarian cancer is critical because the first-line setting offers the greatest potential to impact patient survival,” Paul DiSilvestro, investigator from the SOLO-1 trial, said in a statement.

Currently, Lynparza has the leading market share in HRD-positive ovarian cancer. But its lack of an indication in HRD-negative cases has given GSK’s Zejula that entire part of the market.

Lynparza does boast the distinction of being the only PARP inhibitor allowed in prostate cancer with homologous recombination repair (HRR) mutations, but one of its recent expansion bids failed.

Merck recently stopped the Keylynk-010 trial that was evaluating Lynparza in tandem with PD-1 inhibitor Keytruda in previously treated metastatic castration-resistant prostate cancer (mCRPC) regardless of their tumor’s HRR status. Currently, Lynparza monotherapy is allowed in HRR-mutated cases.

Indeed, compared with either Johnson & Johnson’s Zytiga or Astellas and Pfizer’s Xtandi, the Lynparza-Keytruda combo offered no benefits. Patients on the Merck combo went 4.4 months without disease worsening, versus 4.2 months for the hormonal agents. The combo only cut the risk of death by a negligible 6%.

Similar to single-agent Lynparza, the Lynparza-Keytruda combo showed much better results in HRR-mutated patients with a 47% reduction in the risk of disease progression or death. However, that analysis wasn’t powered to show statistical significance. And the combo didn’t really offer any notable survival benefit in this patient subgroup, the trial investigators noted.

Ebbinghaus noted that the control arm of hormonal therapies in Keylynk-010 outperformed past data but admitted that Lynparza-Keytruda didn’t pass muster in the prostate cancer trial. He also pointed to some “directionally interesting activities” in HRR-mutated patients.

The Keylynk-010 flop comes after Lynparza, used on top of Zytiga and a steroid, successfully extended progression-free survival in patients with newly diagnosed mCRPC in the phase 3 PROpel trial regardless of HRR status. But it also comes as Keytruda has failed in another mCRPC trial when used alongside chemotherapy.

As Ebbinghaus noted, Merck still has one more concept for Keytruda in prostate cancer that needs to be tested out. The Keynote-641 and Keynote-991 trials are pairing Keytruda with Xtandi in either mCRPC or metastatic hormone-sensitive prostate cancer.