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Olaparib Safety and Efficacy Data from the PROfound Trial


An overview of safety and efficacy data from the phase 3 PROfound trial evaluating the PARP inhibitor olaparib.

Case Overview:

Initial Presentation (Jan 2017)

A 64-year-old man is found to have a firm bilateral prostate nodule of 1.8 mm on his routine physical exam

Clinical workup

PSA 109.1 ng/mL

Family history of prostate cancer (father, uncle)

Transrectal ultrasound (TRUS)-guided biopsy of the prostate confirms advanced adenocarcinoma of the prostate and Gleason score of 8 (4 + 4)/Grade Group 4

MRI is negative for pelvic LN involvement but positive for one 1.1-cm mediastinal supraclavicular LN (T2bN0M1a)

His ECOG PS is 1

Germline multigene testing of biopsy specimen revealed a BRCA2 mutation

Initial Treatment (starting Feb 2017)

Patient was started on leuprolide and abiraterone; scheduled for physical exam, PSA assessment, and imaging every 3 months.

By the second follow-up visit (6 months after initiating treatment; August 2017), PSA levels declined to 2.1 ng/mL and prostate nodule size was 1.4 mm.

Patient’s disease remained stable through August 2018 (18 months of treatment).

21- and 24-month Follow-up Notes (November 2018, February 2019)

Patient’s PSA levels increased to 46.9 ng/mL in 11/2018 and 73.7 ng/mL in 2/2019.

MRI revealed that the size of the existing positive LN increased to 1.3 cm, and revealed a new, faintly positive 0.9-cm para-aortic LN.

Given the recent findings and the patient’s known BRCA2 mutation status, the patient and clinician decide to initiate olaparib 300 mg BID.

Neal Shore, MD, FACS: Let’s discuss the PROfound trial and olaparib. I was proud to be part of that trial and on the steering committee, and it was brilliantly led by Johann de Bono, [MD, PhD,] and Maha Hussain, [MD]. These were patients who had mCRPC [metastatic castration-resistant prostate cancer] who had progressed on either abiraterone or enzalutamide. Then there was a cohort A and a cohort B. All the patients who were screened, several thousand patients, they ultimately through tissue testing had to have 1 of 15 homologous recombinant repair [HRR] gene alterations. Cohort A was the BRCA1, BRCA2, ATM, and that was selected because of several earlier phase 2 studies showing significant response to PARP inhibitors for patients who had those 3 particular gene alterations. Twelve other gene alterations went into cohort B. Within cohort A and cohort B, patients were then again randomized 2:1 to receive either the PARP inhibitor olaparib or the physician’s choice, which essentially was if you’d had abiraterone, you’d get enzalutamide. If you’d had enzalutamide, you’d get abiraterone. Some have said, why didn’t you use a taxane comparator? A lot of patients were not taxane eligible. Many of the patients had already had taxanes, and some refused taxanes. And in the real world we oftentimes see this sequencing of one novel hormonal agent to another. I personally almost never do that because I think that’s pretty much a lateral move. But nonetheless, it is done pretty consistently in the real world.

What we were able to demonstrate was, with blinded independent central review and local review, a statistically significant rPFS [radiographic progression-free survival] benefit in cohort A. We subsequently looked at a secondary end point, which demonstrated statistically significant overall survival benefit in this heavily pretreated, heavy tumor burden population. That’s why it resulted in 2 New England Journal of Medicine publications. The safety and adverse effect profile was very consistent with what we’d known for the class of PARP inhibitors. These are oral drugs. The most common unique adverse event of interest is some early onset of anemia, and therefore a CBC [complete blood count] should be checked monthly. This was a global study. All of the patients who were enrolled had to have HRR mutations based on tissue. We obtained a blood-based sampling and ultimately looked at that later, and there was about an 80% concordance, which is good to know if you can’t get tissue, archival or fresh, or metastasis-directed. You can still get blood-based sampling.

What about the adverse events in terms of interruptions and discontinuations? There were some patients, if they had anemia or occasionally some GI [gastrointestinal] adverse effects, there was a very small, single-digit percentage of patients who had pulmonary emboli. We were looking for that. Many of these were asymptomatic, if not most. We didn’t see an increase ultimately in significant grade 3 or 4 cardiovascular events, but the nice thing about the 300-mg BID [twice a day] formulation is you can dose reduce. The drug comes in 150- and 100-mg formulations, so you can play with a 150- to a 100-mg dosage. You can go from 2 to 1, 2 in the morning, 1 in the evening, different dosing. There is a lot of good flexibility. I think the good news is it was only in low single-digit percentages that patients actually discontinued therapy based upon adverse events. This is exactly what I’ve seen in my clinical practice.

What are some strategies to mitigate or manage the adverse effects? We check a CBC monthly. If you have to do a transfusion, you can. I’ve found it very infrequent. I’ve not had much challenge with thrombocytopenia or neutropenia. Of course, when we use radiopharmaceutical therapies, when we use taxane therapies, these are the same kind of things that we think about as it relates to GI toxicities, nausea, diarrhea. It’s all the normal, good strategies one would use, light diets, liquid diets, and various antiemetic therapies. But overall, I’ve not found the grade 3/4 [adverse events] to be particularly problematic. But of course, it’s still something you want to have in that important patient-physician shared decision-making discussion.

Transcript edited for clarity.

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