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Merck's Keytruda Flunks Another Prostate Cancer Test

Prostate cancer has proved an elusive target for cancer immunotherapies, and Merck & Co's checkpoint inhibitor Keytruda is the latest to fall short in the disease in a phase 3 trial.

Merck has said it will abandon the KEYNOTE-991 study of PD-1 inhibitor Keytruda (pembrolizumab) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) after it showed no benefit on either overall survival (OS) or radiographic progression-free survival (rPFS) when the data was analysed midway though.

The company will, however, draw some comfort from the results of a phase 3 trial in biliary tract cancer (BTC), which has given Keytruda a chance of becoming the first rival to AstraZeneca's PD-L1 inhibitor Imfinzi (durvalumab) in this rare and aggressive form of cancer with limited treatment options.

The disappointing prostate cancer data follows two other failed trials reported last year, namely the KEYNOTE-921 study of Keytruda plus chemotherapy in metastatic castration-resistant prostate cancer (CRPC) previously treated with hormonal therapies, and the KEYLYNK-010 trial of Keytruda and Merck/AstraZeneca's PARP inhibitor Lynparza (olaparib) in CRPC patients previously treated with hormonal therapy and chemo.

It leaves the KEYNOTE-641 trial of the PD-1 inhibitor plus enzalutamide in post-hormonal therapy metastatic CRPC patients as Keytruda's last late-stage study in prostate cancer, due to generate results later this year, although Merck has a couple of phase 2 studies ongoing of Keytruda combinations used as later-line CRPC therapy.

The company's head of clinical research, Scot Ebbinghaus, said Merck will "continue to advance our clinical development programme to evaluate Keytruda-based combinations and novel candidates for patients with prostate cancer."

Merck isn't alone in struggling to make headway for its checkpoint inhibitor in prostate cancer, with a litany of other discouraging studies in recent years. The cancer is particularly challenging for immunotherapy, as it tends to have fewer mutations than other cancers, presenting fewer targets for immune cells, and tends to be immunologically 'cold', with few immune cells infiltrating the tumour.

One glimmer of hope came from the CheckMate 650 trial of Bristol-Myers Squibb's PD-1 drug Opdivo (nivolumab) and CTLA4 inhibitor Yervoy (ipilimumab).

The combination showed modest efficacy with an objective response rate of 25%, but was associated with considerable side effects that forced a change in dosing regimen. It remains ongoing with updated results due in the coming months.

BTC study positive

In the BTC trial – codenamed KEYNOTE-966 – a combination of Keytruda with chemotherapy showed a "statistically significant and clinically meaningful" improvement in overall survival versus chemo alone in newly diagnosed patients, and will form the basis of regulatory filings.

Only the top-line result is available at the moment, so the big question is whether Keytruda can do better in BTC than Imfinzi, which improved OS by 20% when added to chemo in the TOPAZ-1 trial reported in 2021. That earned Imfinzi an FDA approval as the first immunotherapy for BTC last September.

Merck Shares Positive Phase 3 Results For Keytruda/Lynparza Regimen In Ovarian Cancer

Merck & Co – known as MSD outside of the US and Canada – has shared positive results from a late-stage trial of a Keytruda (pembrolizumab)/Lynparza (olaparib) regimen as a first-line treatment for advanced ovarian cancer.

The phase 3 KEYLYNK-001 trial has been evaluating Merck's anti-PD-1 therapy Keytruda in combination with chemotherapy followed by maintenance with the company's AstraZeneca-partnered PARP inhibitor Lynparza, with or without bevacizumab, in patients with advanced epithelial ovarian cancer without BRCA mutations.

The study met its primary endpoint, with the Keytruda/Lynparza regimen demonstrating a statistically significant and clinically meaningful improvement in progression-free survival compared to chemotherapy alone.

The study did not reach its secondary endpoint of overall survival, however, with Merck noting that the role of Keytruda in the intention-to-treat population "remains uncertain at this time".

Ovarian cancer, which usually begins in the fallopian tubes or on the outer surface of the ovaries, is the second most common gynaecological malignancy and seventh most common cancer in women globally. Approximately 19,680 cases of the disease are expected to have been diagnosed in the US by the end of 2024.

Keytruda is designed to increase the ability of the body's immune system to help detect and fight tumour cells, while Lynparza prevents the DNA of cancer cells from being repaired, preventing them from growing and spreading.

Keytruda already holds approvals to treat a wide range of cancers, including specific cases of breast, cervical and bladder cancer, but is not approved for use in ovarian cancer. Lynparza, however, has three approved indications in ovarian cancer in the US.

Merck said the results from KEYLYNK-001 will be presented at an upcoming medical meeting and discussed with regulatory authorities.

"For people living with ovarian cancer, there remains an unmet need for new treatment options that have the potential to improve outcomes," said Gursel Aktan, vice president, global clinical development, Merck Research Laboratories, adding that KEYLYNK-001 is the first positive phase 3 trial for Keytruda plus Lynparza.

The results come two months after Merck shared positive results from the phase 3 KEYNOTE-689 trial of Keytruda as a perioperative treatment for patients newly diagnosed with stage 3 or 4A, resected, locally advanced head and neck squamous cell carcinoma.

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