Prostate cancer is giving Merck & Co.’s seemingly unstoppable Keytruda a hard time. But even after three pivotal trial flops in less than a year, the New Jersey drugmaker is still hopeful that the PD-1 king can eventually crack the tumor type one way or another.
Merck is supportive of its prostate cancer program and is still standing behind a fourth phase 3 trial of Keytruda in the indication that remains ongoing, Scot Ebbinghaus, M.D., vice president of clinical research at Merck Research Laboratories, said in an interview with Fierce Biotech.
Ebbinghaus defended Merck’s decision back in 2019 to bet heavily on Keytruda’s prostate cancer clinical development program with four phase 3 trials launched almost simultaneously. Three of them have since returned negative.
“That’s kind of ‘history is written by the victors,’ I guess,” Ebbinghaus said. “It’s always the question, when a phase 3 doesn’t work out, you go back and take a hard look and ask yourself, did you make the right decisions, was the data upon which you based your development plan sound? And all of those things, like everyone, we’ve gone through those exercises.”
Ebbinghaus wouldn’t put a number to the pivotal trials one could launch for a drug based on an early trial signal. “But I think we made the right decision to go into prostate cancer with a relatively aggressive approach given the data that we had, given the unmet need and given the overall success of the Keytruda program,” he said.
To Ebbinghaus, it’s important to “push the envelope and explore the boundaries of” where immunotherapies work. Those phase 3 trials represent Merck’s effort to “give prostate cancer every shot at potentially showing the benefits” of Keytruda, he said.
Ebbinghaus made the comment as data detailing a Keytruda flop in metastatic castration-resistant prostate cancer (mCRPC) were shared at the 2023 ASCO Genitourinary Cancers Symposium.
The addition of Keytruda to the chemotherapy docetaxel failed to improve upon chemo alone in terms of extending the lives of mCRPC patients who had previously received next-generation hormonal agents. Nor did the Keytruda-docetaxel combination significantly delay the time to disease progression or death, even though the results favored the Keytruda regimen.
Specifically, in the KEYNOTE-921 trial, patients who received the Keytruda-docetaxel combo lived a median 19.6 months, versus 19 months for the docetaxel arm, leading to a mere 8% decreased risk of death. The median radiology progression-free survival clocked in at 8.6 months for the experimental therapy, compared with 8.3 months for chemo alone, which translated into a nonsignificant 15% improvement.
KEYNOTE-921 marked the second Keytruda setback in prostate cancer in less than a year. Before it, the KEYLYNK-010 trial failed to find the combination of Keytruda and the AstraZeneca-partnered PARP inhibitor Lynparza could offer disease progression or survival benefit over standard androgen-directed therapies in mCRPC. The combo only cut the risk of death by 6% over either Johnson & Johnson’s Zytiga or Astellas and Pfizer’s Xtandi.
In a third flop, Merck recently pulled the plug on KEYNOTE-991 after an independent data monitoring committee ruled that Keytruda’s addition to Xtandi and androgen deprivation therapy couldn’t offer enough benefit in metastatic hormone-sensitive prostate cancer.
Still, Merck is waiting on data from the KEYNOTE-641 study, which tests Keytruda with Xtandi in mCRPC. The trial remains ongoing as its data monitoring committee reviews the data every six months to evaluate whether the trial should proceed, Ebbinghaus noted.
Merck launched those four prostate cancer trials in close succession around 2019 mainly based on encouraging data from an early-phase trial coded KEYNOTE-365.
The basket trial is still open, where Merck is exploring additional combinations as well as certain subsets of prostate cancer which Keytruda could work in. Ebbinghaus noted that Merck has some promising early data in neuroendocrine prostate cancer, an aggressive variant of the tumor type.
Outside of Keytruda, Merck plans to start a phase 3 for a prostate cancer candidate it recently in-licensed from Orion for $290 million upfront, Ebbinghaus said, although he wouldn’t divulge the exact trial design.