Advanced Prostate Cancer
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ASCO Genitourinary Cancers Symposium (Olaparib and Durvalumab in metastatic castrate-resistant prostate cancer (mCRPC))

Small study but interesting results.

Olaparib is a PARP inhibitor [1]; Durvalumab is a checkpoint inhibitor [2].

Olaparib [Lynparza] has had success in men with hereditary BRCA1 or BRCA2 mutations.

As wonderful as newer drugs such as Zytiga are, resistance can lead to the emergence of cells that are very difficult to manage.

"Data suggests 25-30% of sporadic mCRPC has defects in DNA repair pathways which may confer sensitivity to PARP inhibition". "We hypothesize that increased DNA damage by olaparib (O) will complement anti-tumor activity of immune checkpoint blocking antibody, durvalumab (D), in mCRPC." [3]

"8/17 pts{patients} (47%) had PSA responses >50%.

"6 of these pts had mutations in the DNA damage repair pathways ..."

"2/17 pts (11%) had PSA responses >30% with no known mutations in DNAdr."

Note that this was in an "unselected population".

While most of us do not have hereditary BRCA mutations, men who ultimately fail Zytiga/Xtandi might nonetheless respond to Olaparib.

-Patrick

[1] en.wikipedia.org/wiki/Olaparib

[2] en.wikipedia.org/wiki/Durva...

[3] 163 Oral Abstract Session, Thu, 1:00 PM-2:30 PM and Poster Session

(Board #A7), Thu, 11:30 AM-1:00 PM and 5:15 PM-6:15 PM

A phase 2 study of olaparib and durvalumab in metastatic castrate-resistant prostate cancer (mCRPC) in an unselected population.

Fatima Karzai, Ravi Amrit Madan, Helen Owens, Anna Couvillon, Amy Hankin, Monique Williams, Marijo Bilusic, Lisa M. Cordes, Jane B Trepel, Keith Killian, Paul S. Meltzer, James L. Gulley, Jung-min Lee, William L. Dahut; National Cancer Institute at the National Institutes of Health, Bethesda, MD; National Cancer Institute, Bethesda, MD; Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; National Institutes of Health, Bethesda, MD; Center for Cancer Research, National Cancer Institute at the National Institutes of Health, Bethesda, MD; Center of Cancer Research, Bethesda, MD; Center for Cancer Research, National Cancer Institute, Bethesda, MD; National Cancer Institute Women’s Malignancies Branch, Bethesda, MD

Background: Data suggests 25-30% of sporadic mCRPC has defects in DNA repair pathways which may confer sensitivity to PARP inhibition (PARPi). Immune checkpoint blockade may increase the proportion of patients that respond to PARPi. We hypothesize that increased DNA damage by olaparib (O) will complement anti-tumor activity of immune checkpoint blocking antibody, durvalumab (D), in mCRPC (NCT02484404).

Methods: Single arm pilot study with accrual of 25 patients (pts) with mCRPC and disease that is amenable to biopsy. Prior treatment with enzalutamide and/or abiraterone is required. D is given at 1500 mg iv q28 days + O 300 mg tablets po q12 hours. The primary endpoint is PFS. Core biopsies undergo mutational analysis.

Results: In the first 17 pts, median age is 66 (range 45-79 years), median baseline PSA is 79.67 ng/mL [3.93-2356 ng/mL]). Median Gleason score is 8. 6 patients have bone only disease and 11 patients have bone and soft tissue/visceral disease. Median number of cycles is 7 (2-17). Grade 3/4 adverse events include anemia 4/17 (24%), lymphopenia 2/17 (12%), infection 2/17 (12%), thrombocytopenia, leukopenia, neutropenia, nausea, vomiting, UTI, hypertension, hearing impairment, fatigue, syncope, oral mucositis, muscle weakness, and muscle cramps [1/17 each, (6%)]. 8/17 pts (47%) had PSA responses .50%. 6 of these pts had mutations in the DNA damage repair pathways (DNAdr). 2/17 pts (11%) had PSA responses .30% with no known mutations in DNAdr. 4 pts had a PR. The 12 month PFS is 51.5% (95% CI: 25.7-72.3%).

Conclusions: Preliminary data shows D+O is well tolerated with activity in an unselected population. Accrual is ongoing with biomarker analysis. Clinical trial information: NCT02484404.

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Patrick -

is it the luck of the draw or this year ASCO papers are more focused on non-metastatic advanced PCa?

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I took the papers in sequence, & non-mPCa came first, but I do believe there is a push to treat high-risk cases more aggressively.

Cynics might say that BigPharma is trying to expand the market for its wares.

However, it could be argued that the target includes men who may already have mets, except that you can't see them yet.

-Patrick

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