Immunotherapy may halt spread of prostate cancer — UK trial

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More than a third of men with an advanced form of prostate cancer were still alive and one-in-10 had not had further growth after a year on the drug pembrolizumab, an Institute of Cancer Research trial found.

It is the first time immunotherapy has been shown to benefit some men with prostate cancer, the researchers said.

The trial of 258 men led by a team at the Institute of Cancer Research, London, and the Royal Marsden NHS Foundation Trust, will be presented at the American Society of Clinical Oncology annual meeting in Chicago.

Professor Johann de Bono, director of the drug development unit, said: “In the last few years immunotherapy has changed the way we treat many advanced cancers but up to now no one had demonstrated a benefit in men with prostate cancer.

“Our study has found that immunotherapy can benefit a subset of men with advanced, otherwise untreatable prostate cancer, and these are most likely to include patients who have specific DNA repair mutations within their tumours.”

Immunotherapy drugs work by stimulating the immune system to recognise and fight the cancer. They are used to treat some advanced cancers, including lung.

The report says the trial found the men lived much longer when treated with “checkpoint inhibitor” pembrolizumab. About 38% were still alive after a year and 11% did not see the cancer grow.

Previous trials using immunotherapy in prostate cancer have been unsuccessful but the latest research examined the genetics of the tumours and found particular groups of patients may benefit.

While only 5% of men in the trial saw their tumours shrink or disappear after treatment, many of those had mutations in genes involved in repairing DNA in their tumours.
The researchers suggest these mutating cancer cells may be easy for the immune system to recognise and attack because they look different from healthy cells.

Data from some other cancer types, such as bowel, has similarly shown tumours with defects in DNA repair mutations are more susceptible to immunotherapy. De Bono said: “We are planning a new clinical trial, specifically in men with prostate cancer whose tumours have mutations in DNA repair genes, to see if immunotherapy can become a standard part of their treatment.

“It’s exciting that immunotherapy could offer some men more time with their loved ones where they have such advanced disease that they have run out of existing treatment options.”

Only about 20% of cancer patients respond to immunotherapy – something that researchers do not fully understand.

Professor Paul Workman, CEO of the Institute of Cancer Research said in the report: “Immunotherapy has proven to be a smarter, kinder treatment for many types of cancer but it still only works for a minority of patients.

“The challenges we now face are how to predict in advance who will benefit, and how to make immunotherapy work for more people.

“This new trial has found that testing for mutations in DNA repair genes could be valuable marker of who will respond.

“If we can prove that in the planned new trial, it should be possible to provide some men with advanced prostate cancer with an exciting new treatment option.”

The report says research will now focus on identifying markers to help pick out the prostate cancer patients whose tumours are most likely to shrink after immunotherapy treatment.

Background: Efficacy of PD-1 inhibition has not been demonstrated in large-scale mCRPC trials. Pembro showed preliminary antitumor activity in PD-L1+ mCRPC in KEYNOTE-028 (n = 23). Here, we present results from cohorts 1-3 (n = 258) of the phase 2 KEYNOTE-199 study of pembro monotherapy in docetaxel-refractory mCRPC (NCT02787005).
Methods:Cohorts 1 (C1) and 2 (C2) enrolled patients (pts) with RECIST-measurable PD-L1+ and PD-L1– disease, respectively. C3 enrolled pts with nonmeasurable, bone-predominant disease. All pts had ECOG PS 0-2 and received ≥1 novel endocrine therapy (eg, abiraterone, enzalutamide) and 1-2 prior chemotherapies including docetaxel. Pts received pembro 200 mg Q3W until PD or intolerable toxicity. Response was assessed Q9W in yr 1, then Q12W. Primary end point was ORR per RECIST v1.1 by central review in C1 and C2, separately and combined. Key secondary end points included DCR (CR + PR + SD) per PCWG3-modifed RECIST and safety in all 3 cohorts.
Results: 131 pts enrolled in C1, 67 in C2, and 60 in C3. Median follow-up as of Oct 13, 2017, was 8.1 mo, 7.9 mo, and 11.8 mo, respectively. Antitumor activity was observed in all cohorts (Table). Across cohorts, DCR lasting ≥6 mo was 11%. In C1 and C2, 9% of pts had a ≥30% decrease in target lesions; 48% had target lesion changes between –30% and +20%. The response rate was numerically higher in pts with somatic BRCA1/2 or ATMmutations (12%). Drug-related grade 3-5 AE rates were 13% in C1, 12% in C2, and 17% in C3.
Conclusions: Pembro shows antitumor activity and disease control with acceptable safety in pts with docetaxel-refractory mCRPC, regardless of PD-L1 status, in both RECIST-measurable and nonmeasurable disease. These data support further evaluation of pembro in mCRPC, including in pts wth homologous recombination defects.

Johann S De Bono, Jeffrey CH Goh, Kristiina Ojamaa, Jose Maria Piulats Rodriguez, Charles G Drake, Christopher J Hoimes, Haiyan Wu, Christian Heinrich Poehlein, Emmanuel S Antonarakis

The Guardian report ASCO 2018 abstract

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