In rare flop, Merck calls it quits on Keytruda-Lynparza combo in prostate cancer

The combination of two powerful drugs with excellent clinical track records isn’t necessarily a guarantee for success.

Case in point: Merck & Co. just found out that a pairing of Keytruda and Lynparza wasn’t any better than an anti-androgen therapy in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC).

Compared with either Johnson & Johnson’s Zytiga or Astellas and Pfizer’s Xtandi, the Keytruda-Lynparza combo failed to further extend patients’ lives, nor did it stall tumor progression. All patients had prior chemo treatment and one of the two hormone therapies. To make things worse, the Merck combo also showed a higher rate of grade 3 to 5 drug-related serious side effects.

After the interim analyses of the phase 3 Keylynk-010 trial returned the bad news, Merck has decided to follow the recommendation of an independent data monitoring committee and pull the plug on the trial early.

The flop comes as a bit of surprise, as Lynparza monotherapy has been allowed to treat patients with homologous recombination repair gene-mutated mCRPC who have progressed following prior treatment with Xtandi or Zytiga.

It also comes on the heels of a Lynparza win in newly diagnosed mCRPC. The AstraZeneca-partnered PARP inhibitor showed that its addition to Zytiga and a steroid reduced the risk of disease progression or death by 34% in that patient group, regardless of gene mutation status.

Both Keytruda and Lynparza are considered the leaders in their respective fields—Keytruda is undoubtedly the PD-1 king, and Lynparza is the best-selling PARP inhibitor. 

Despite the prostate cancer miss, Merck has multiple Keylynk studies evaluating the Keytruda-Lynparza combo in different lung cancer settings, ovarian cancer and triple-negative breast cancer, as well as across solid tumors with certain biomarkers, the company noted.

And besides its AZ partnership, Merck is evaluating Keytruda in several other combinations in mCRPC. The phase 3 Keynote-921 trial is pairing the popular PD-1 inhibitor with chemo in patients who’ve progressed on next-generation hormonal agents like Zytiga and Xtandi. The trial bears a primary completion date in September 2021, but Merck has yet to publicize the results.

In addition, Keynote-641 is testing whether Keytruda’s combo with Xtandi could beat Xtandi alone in mCRPC. Another Keynote-991 study is adding Keytruda to Xtandi and androgen deprivation therapy in patients with metastatic hormone-sensitive prostate cancer.

Meanwhile, Keytruda’s PD-1 rival, Opdivo from Bristol Myers Squibb, has partnered with Clovis Oncology’s Rubraca, a PARP inhibitor that has underwhelmed thanks to commercial pressure from Lynparza and GlaxoSmithKline’s Zejula. A phase 2 trial dubbed CheckMate 9KD recently showed a survival benefit for the Opdivo-Rubraca combo in patients with chemotherapy-naïve mCRPC with homologous recombination deficiency. 

For its side, AZ has also been pairing Lynparza with its PD-L1 inhibitor Imfinzi. For one area that it might clash with Merck, the phase 3 Duo-O study is testing Lynparza, Imfinzi and Roche’s Avastin in ovarian cancer.