Prostate cancer: Maximising approved drugs’ potential and first signal immunotherapy works

Keytruda research marks the first time PD-1 checkpoint inhibitor has produced a response in prostate cancer
Insight offered into how Zytiga may interact with different populations, underscoring the importance of genetically diverse studies
Testing circulating tumour cells may allow physicians to predict which patients will respond to Zytiga and Xtandi

For the first time, an immunotherapy has shown promise in prostate cancer in data announced at ASCO 2018. Richard Staines reports on research presented at the conference, where scientists also showed that approved drugs may have untapped potential.

Drugs such as Janssen’s Zytiga (abiraterone acetate), and Pfizer/Astellas’ Xtandi (enzalutamide) have been the story of prostate cancer treatment for the last few years, but could this be about to change?

Immunotherapies have been shown to be highly effective in many forms of cancer except prostate, where they have so far not been able to produce significant results. Now a new trial, conducted partly in the UK, seems to suggest that certain patients with prostate cancer may benefit from treatment with Merck & Co’s Keytruda (pembrolizumab) PD-1 checkpoint inhibitor.

Keytruda research was ubiquitous at ASCO this year, but the results from a prostate cancer study raised eyebrows because it is the first time this class of drug has produced a response in metastatic castration-resistant prostate cancer (mCRPC).

In the KEYNOTE-199 study, involving 131 patients, there were two cohorts with measurable PD-L1 positive and PD-L1 negative disease respectively, while a third had non-measurable, bone-predominant disease. All patients had been treated with one or more novel endocrine therapy – Zytiga or Xtandi and one or two chemotherapies including docetaxel.

Patients received Keytruda every three weeks until death or intolerable toxicity, and the study’s primary goal was overall response rate, with secondary endpoints of disease control and safety. Results after follow-up of 8–12 months showed that a disease control rate lasting more than six months was 11%. In the first two cohorts 9% of patients saw their tumours shrink by 30% or more, and 48% had target lesion changes between –30% and +20%. The response was numerically higher in patients with somatic BRCA1/2 or ART mutations, and moderate to severe drug-related adverse events occurred in 13% in cohort 1, 12% in cohort 2, and 17% in cohort 3.

Study authors concluded that Keytruda showed antitumour activity and disease control with acceptable safety in the trial, regardless of PD-L1 status. They added that findings support further studies in the indication.

Roy Baynes, Merck’s head of global clinical development, noted the results in an interview with pharmaphorum, although gave no indication about whether the company has plans for further trials. Standing on the side-lines of the ASCO conference he acknowledged “there is a signal there”.

Zytiga may be more effective in black men than white men

ASCO also provided insight into how currently-approved prostate cancer drugs may interact with different population groups.

One trial, from Duke University in Durham, North Carolina, found black men were more likely to have a decline in an indicator of prostate cancer response than white men when treated with Zytiga. The study was the first prospective study to compare outcomes of Zytiga for advanced prostate cancer in black men and white men, the trial authors said. Their findings confirm previous retrospective observations suggesting a stronger cancer response to Zytiga in black men.

The study sought to address the issue of under-representation of ethnic minorities in clinical trials – in most the percentage of minority participants, including black patients, is disproportionately lower than the representation of the same racial group in the general population. Black men were also under-represented in the trial that led to Zytiga’s approval in this indication, mCRPC.

Called Abi Race, the new study enrolled 100 men with mCRPC, of whom 50 self-identified as white and 50 self-identified as black. They received standard treatment of Zytiga and prednisone until the cancer worsened or unacceptable side effects occurred. Researchers also did exploratory research on genetic ancestry, as well as differences on genomic markers, metabolism and hormone levels.

Although time to radiographic progression was similar between the two groups, when researchers looked at prostate-specific antigen (PSA), a marker of cancer response and progression, they found differences by race.

Zytiga was more effective at both lowering PSA and delaying PSA progression in black men than in white men. After treatment 48% of black men had a PSA decline of 90% or more, compared with 38% of white men. More than three quarters (76%) of black men saw their PSA levels halved, compared with 66% of white men, and 86% of black men saw their PSA levels decline by 30% or more, compared with 76% of white men.

The researchers are co-leading an initiative to study all treatments of men with advanced prostate cancer using a global registry of 5,000 patients called IRONMAN. While the study is relatively small, its results suggested that biology driving advanced prostate cancer may be different in black and white men. But the research also suggests that black men may also be a group of patients more likely to respond to therapy.

Study author Daniel George, professor of medicine and surgery at Duke University, said: “Black men are more than twice as likely to die of prostate cancer than white men and are generally thought to have worse prostate cancer outcomes. Our study suggests that when black men and white men with advanced prostate cancer are given the same treatment this is not the case.

“Our research underscores the importance of specifically studying genetically diverse populations and raising awareness of these results, so that everyone who can benefit from abiraterone is offered this treatment.”

Circulating tumour cells

Further research published at ASCO suggested that it may be possible to predict which patients will respond to Zytiga and Xtandi by testing circulating tumour cells for the presence of a variant androgen receptor known as AR-V7, which is one of the most clinically investigated variant receptors found in prostate cancer patients.

The research, which also came from Duke University, showed that the presence of AR-V7 in circulating tumour cells is positively associated with resistance to these two staple prostate cancer drugs.

The PROPHECY trial involving 188 men with progressive metastatic disease found extreme differences in outcomes depending on presence of the antigen. The trial compared two assays for AR-V7 before and after progression on Xtandi or Zytiga, then once again after patients had taxane therapy. Men with tumour cells in their blood expressing AR-V7 had a 0% PSA response rate compared with 53% of men without AR-V7. Median overall survival was 27.2 months without AR-V7, compared with only 10.8 months with AR-V7, although there was a large variance in overall survival between the two assays.

Dr Andrew Armstrong, an oncologist from Duke Cancer Institute, said that detecting presence of AR-V7 may well be useful when treating patients with mCRPC.

While the immunotherapy result is interesting, the conference showed that improving treatment strategies with Xtandi and Zytiga could raise the bar even higher in terms of prostate cancer outcomes.

Richard Staines is Senior Reporter at pharmaphorum. He has been a journalist since the 1990s and has written for websites, newspapers and magazines. He has always had an interest in health, and has been focusing on the pharma industry since 2010, interviewing industry leaders and covering stories on topics including regulation, mergers and acquisitions, and the latest clinical developments.

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