KEYNOTE-365 Cohort A: Pembrolizumab plus olaparib in docetaxel-pretreated patients with mCRPC

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Published: 18 Feb 2019
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Prof Evan Yu - Fred Hutchinson Cancer Research Center, Seattle, USA

Prof Evan Yu speaks to ecancer at the 2019 ASCO Genitourinary Cancers Symposium about Cohort A of the KEYNOTE-365 study which looked at the combination of pembrolizumab plus olaparib in docetaxel-pretreated patients with metastatic castrate-resistant prostate cancer (mCRPC).

He explains that these patients were docataxel-pretreated for mCRPC and were treated with pembrolizumab IV 200mg every 3 weeks and olaparib 400mg twice daily.

Prof Yu reports that, although there was a confirmed response rate of near 12%, around half the patients had a PSA decline.

He therefore believes there is some work to do in order to understand why there is a better initial response compared with later on in the cycle.

We did a study called KEYNOTE-365 and this was a combination trial where there were multiple different cohorts. What was reported here was a cohort of enzalutamide plus pembrolizumab, docetaxel plus pembrolizumab and a cohort in which I gave an oral presentation at was olaparib plus pembrolizumab. Now, these patients were in the post-docetaxel disease state, they received docetaxel for metastatic castration resistant prostate cancer, were allowed to receive up to one other chemotherapy like cabazitaxel, and they could have received up to two secondary hormonal therapies like abiraterone and enzalutamide. This was a molecularly unselected patient population and they were treated with pembrolizumab IV, 200mg IV every three weeks, and olaparib 400mg p.o. b.i.d. They received that with regular RECIST response monitoring, Prostate Cancer Working Group 3 monitoring, and what we found was a PSA response rate, confirmed response rate, of around 12%. That being said and done, we saw about half the patients actually have a PSA decline so it was just the confirmed response was 12%.

We found a similar trend with the soft tissue disease where we saw about 29% had at least 30% or greater shrinkage of disease but the confirmed response rate was 7%. So we have some work to do in regards to what’s going on with why we’re getting better initial responses but we’re not able to confirm that later.

We did do some molecular analysis, we did Guardant360 for circulating tumour DNA and we did not definitively find anyone with any homologous recombination deficiency. We also did whole exome sequencing on patients that we had soft tissue on and that was, unfortunately, only 17 of the patients. We found one patient with a BRIP1 frame-shift mutation but we couldn’t confirm that with biallelic. So it was probably a very, very low homologous recombination deficiency population. We didn’t definitively identify any but I can’t say for certain that there weren’t a couple of patients in there.

It was very safe and tolerated; 15% had immune-mediated adverse events, all grade 1 or 2. So the plan is to expand this cohort that is currently 42 patients out to 100 patients and to do a randomised phase III study in the post-docetaxel space, post either abiraterone or enzalutamide and they will be randomised to pembrolizumab olaparib versus the other drug – if you received abiraterone you’d have enzalutamide; if you received enzalutamide you’d have abiraterone.