Pembrolizumab tested in previously treated mCRPC
medwireNews: The PD-1 inhibitor pembrolizumab shows antitumor activity in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC), indicate results from the KEYNOTE-028 and KEYNOTE-199 trials.
The objective response rate (ORR) was around 17% in the prostate cancer cohort of the phase I KEYNOTE-028 study that enrolled only men with programmed cell death ligand 1 (PD-L1) expression levels of at least 1%, and in the range of 3–5% in the phase II KEYNOTE-199 trial that did not restrict recruitment by PD-L1 expression.
Agreeing that the ORRs are not as dramatic as those seen in other tumor types with pembrolizumab, genitourinary medical oncologist Douglas McNeel (University of Wisconsin School of Medicine and Public Health, Madison, USA) told medwireNews that although the findings are not “overwhelming,” they do represent “a foundation for building on.”
In light of these results, he believes that pembrolizumab will be “best developed in combination” in prostate cancer. McNeel said that his laboratory is investigating pembrolizumab alongside antitumor vaccines, while the KEYNOTE-365 study is assessing docetaxel, enzalutamide, and olaparib as potential partners for pembrolizumab.
He noted that the stage at which pembrolizumab fits into the treatment armamentarium will depend on the partner; if the best responses are achieved with docetaxel, for example, then it makes sense to use pembrolizumab in later stages, whereas in combination with vaccines, pembrolizumab could potentially be used in very early-stage disease, even before androgen deprivation therapies. At the moment though, “the jury is still out,” McNeel remarked.
The other unknown is which patients are likely to benefit from treatment with pembrolizumab, commented McNeel. Clearly some patients respond, but it is difficult to pinpoint who these patients may be based on the data from these trials, he said.
All 23 men in the prostate cancer cohort of the KEYNOTE-028 trial had failed standard therapy and the majority (73.9%) had received at least two previous treatments for metastatic disease. They were given pembrolizumab 10 mg/kg every 2 weeks for up to 2 years.
Over a median follow-up of 7.9 months, four patients had a partial response that occurred at a median of 2.7 months and lasted for a median of 13.5 months.
And as reported in the Annals of Oncology, the median progression-free survival and overall survival (OS) times were 3.5 and 7.9 months, respectively.
Aaron Hansen (UHN Princess Margaret Cancer Centre, Toronto, Ontario, Canada) and co-investigators note that as tumor PD-L1 expression was used as a selection criterion, the “true response rate in an unselected population is not known.”
They conclude: “Investigation of pembrolizumab monotherapy and in combination with other anticancer agents, in an unselected PD-L1 patient population restricted by prior lines of therapy to permit a homogeneous patient cohort, may identify specific subgroups of patients who might derive benefit.”
Johann de Bono, from the Royal Marsden Hospital in London, UK, reported on three cohorts of the KEYNOTE-199 study comprising patients with docetaxel-refractory mCRPC at the ASCO Annual Meeting 2018 in Chicago, Illinois, USA.
Treatment with pembrolizumab 200 mg every 3 weeks led to two complete and five partial responses among the 131 participants with PD-L1-positive disease and two partial responses among the 67 PD-L1-negative patients. The median duration of response was 8.4 months and unreached, respectively.
The corresponding median OS times were 9.5 and 8.0 months, and although an ORR could not be calculated for the third cohort of 60 men with nonmeasurable, bone-predominant disease, median OS was not reached in these patients.
de Bono concluded that “[f]urther evaluation of pembrolizumab as monotherapy and as part of combination therapy is ongoing,” as is research to identify biomarkers to select patients who may derive benefits.
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