Olaparib Effective in BRCA2-Altered Biochemical Recurrence Post-Prostatectomy in Phase 2 Study - Catherine Handy Marshall

November 4, 2024

Cathy Marshall discusses a non-randomized clinical trial evaluating olaparib without androgen deprivation therapy for high-risk biochemically recurrent prostate cancer following prostatectomy. The study shows promising results, particularly for patients with BRCA2 alterations, where all patients demonstrate PSA-50 responses. The conversation explores the trial design, patient outcomes, and safety profile of olaparib in this setting. Dr. Marshall notes that while standard hormonal therapy typically shows high response rates, olaparib offers a different side effect profile that may benefit asymptomatic patients. The discussion highlights the potential for using PARP inhibitors earlier in the disease course and future research directions, including larger studies and investigation of resistance mechanisms.

Biographies:

Catherine Handy Marshall, MD, MPH, Genitourinary Oncologist, Assistant Professor, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD

Andrea K. Miyahira, PhD, Director of Global Research & Scientific Communications, The Prostate Cancer Foundation


Read the Full Video Transcript

Andrea Miyahira: Hi everyone. I'm Andrea Miyahira at the Prostate Cancer Foundation. Here with me today is Dr. Cathy Marshall of Johns Hopkins University. She will review her recent study, "Olaparib Without Androgen Deprivation for High-Risk Biochemically Recurrent Prostate Cancer Following Prostatectomy," a non-randomized clinical trial. This was recently published in JAMA Oncology. Dr. Marshall, thanks for joining me.

Cathy Marshall: Okay, thanks so much for having me today. So most patients with localized prostate cancer are cured with surgery or radiation therapy, but about 40% will develop biochemical recurrence. So that's BCR, biochemical recurrent prostate cancer, where the PSA is detectable after local therapy in the absence of any metastatic disease defined by conventional scans with CAT scan and bone scan. The natural history of biochemical recurrent prostate cancer is pretty variable. Some patients have pretty prolonged survival while others will develop metastasis pretty quickly. High-risk features that are associated with a faster time to metastatic disease are a short PSA doubling time, a high Gleason score, and a short time from surgery to recurrence. The treatment options for patients now include observation, that's used mostly for those without any high-risk feature, radiation, androgen deprivation therapy, or enzalutamide. PARP inhibitors are not on that list currently; they're approved for men with metastatic castration-resistant prostate cancer in conjunction with ADT and other hormonal agents.

We hypothesized, however, that PARP inhibition would be an alternative treatment strategy to hormonal therapy for men who have high-risk biochemical recurrent prostate cancer. So what we did was a phase two multi-center study. Patients had to have biochemical recurrent prostate cancer after radical prostatectomy. We did this just to ensure that we had available tissue for correlative testing for all patients. We enrolled a high-risk group of patients with a PSA doubling time of less than or equal to six months, and a PSA of at least one nanogram per milliliter. And patients were not on any ADT and had to have testosterone levels over 150 nanograms per deciliter to enroll.

This is a single-arm study. All patients were treated with olaparib, 300 milligrams orally twice a day and were treated until a doubling of their baseline PSA, clinical or radiographic progression, or unacceptable toxicity. The primary endpoint was a PSA-50 response, which is a decline in PSA by at least 50%. And key secondary endpoints were safety and tolerability, time to PSA doubling, PSA progression-free survival, and then metastasis-free survival.

The study design had a stepwise adaptive statistical plan, and there were interim stopping rules to determine the need for study enrichment of the population. The first stage was to enroll 20 biomarker-unselected patients, and because more than two participants had a PSA-50 response—so at least three responses that we saw initially—the study went on to enroll a total of 30 subjects, so an additional 10 patients, and then if the study did not meet its criteria for futility—so there were at least six responses that we saw—then we could expand to enroll the total of 50 subjects in the biomarker-unselected population. So what we considered a positive biomarker were these genes listed here in the HRR, homologous recombination or DNA damage repair pathway. And in our study population and in the trial, the entire trial ended up being an unselected population, so we did not enrich for any of these biomarkers.

A total of 51 patients were enrolled. At the time of analysis, three discontinued due to toxicity, 45 discontinued due to progression of disease, and then three continued on treatment. And we still have a couple of patients on treatment today.

Of the 51 patients enrolled, 27 or a little bit over half were considered to have biomarker. The mean age of the participants was about 64. The median baseline PSA was 2.8, and the mean PSA doubling time was 2.9 months. Gleason grade group 5 disease was present in 11 of the 27 patients in the biomarker-positive group and five of the 24 patients in the biomarker-negative group. So clearly a high-risk population. And then the median time from surgery to study entry was about 4.8 years. Most of the patients in both groups had received prior radiotherapy for biochemical recurrence.

Of the 27 participants in the biomarker-positive group, BRCA2 alterations were the most common. So we had 11 of those patients. ATM and CHEK2 alterations were the next most common; we had six patients with those alterations. And then FANCA alterations among two, and then CDK and FANCE alterations in one patient each. Four of the 51 patients had unknown alterations because of tumor sequencing failure after insufficient isolation of DNA, and 20 patients had negative results.

So this is the waterfall plot showing the best PSA response in this study. Thirteen of 51 patients had a PSA-50 response. There were no PSA-50 responses seen among the 24 participants in the biomarker-negative group. So those are the patients with no alterations in the gray color. Of the 27 patients in the biomarker-positive group, that's where we saw the 13 PSA-50 responses. The navy blue bars are the 11 BRCA2 alterations, and you can see that all of those patients had a PSA-50 response. And then the other PSA-50 responses were seen in one patient with a CHEK2 alteration, and then one patient with an ATM alteration.

This is the spider plot showing the duration of response. I'll just highlight the median response duration of 25 months for those with BRCA2 alterations, and some people had responses even going on upwards of three years.

So here we see the Kaplan-Meier curves for PSA progression-free survival and metastasis-free survival. So first on the left is the graph for PSA progression-free survival. Overall in the cohort, the median PSA progression-free survival was 19 months. The median time to PSA progression in the biomarker-positive group was 22.1 months, and in the biomarker-negative group was 12.8 months. On the right, we have the metastasis-free survival with a median overall metastasis-free survival of 32.9 months. On the blue line are those with the positive biomarker, and the median metastasis-free survival was 41.9 months, and that's compared to 16.9 months for the median metastasis-free survival for those in the HRR-negative group.

Last, we have the median time to next anti-cancer therapy, which overall was 15.4 months. There was a statistically significant longer period in the biomarker-positive group of 22.7 months, which was in the biomarker-positive group. And that's compared to the biomarker-negative group, which had a median time to next cancer therapy of about 12.4 months.

So this is listing the common AEs that we have that were seen in at least three participants. The most common events that we saw were fatigue, nausea, and leukopenia. There were no deaths during the trial. There were two serious adverse events. One was anemia, which was related to study drug, and one was a cerebrovascular accident, which was unrelated to study drug. Three participants I mentioned earlier stopped therapy due to treatment toxicity: two for anemia, one for leukopenia, and then one patient developed a venous thromboembolism that was possibly related to study treatment. But the side effect profile that we saw was pretty consistent with what had been seen previously with olaparib, and there weren't any new safety signals that we observed.

So in conclusion, olaparib has activity in the absence of androgen deprivation therapy for men with BRCA2 alterations in particular, really a modest response amongst those with other HRR mutations, and no activity in those without HRR mutations. So further study probably warranted in this first group and unlikely to be warranted in this last group. And just want to acknowledge patients and their family members, all of the study staff who participated in this, and then funding for the study came from AstraZeneca, Veracyte, and Foundation Medicine, who were partners on the correlative work as well.

Andrea Miyahira: Thank you so much, Dr. Marshall, for sharing this study with us. So how did efficacy compare between patients with BRCA2 or HRR alterations when they're receiving olaparib in the BCR state compared with efficacy observed when olaparib is given later?

Cathy Marshall: So in our study in particular, in the BRCA2 alterations, people have very high responses. So we saw responses in 100% of patients. Later on in the disease course from the other published studies, it's probably closer to about 50% to 60% of men will have responses. The responses are obviously much lower in what we saw and what's published in the other subgroups of patients for ATM and CHEK2. So definitely higher in our population, which of course we need to do larger studies to confirm that, but we also think that maybe there's less tumor heterogeneity in the earlier biochemical recurrent setting, and that may be why we're seeing some of these higher responses compared to when it's used later on in the metastatic castration-resistant setting and why there may be a lower response rate there.

Andrea Miyahira: Thank you for that. So how do responses among HRR carriers in the BCR state being treated with olaparib compare to standard of care?

Cathy Marshall: So in the BCR setting, the standard of care would be considered hormonal therapy. So response rates there are very high, and that's true too even in the HRR setting. The real main reason for doing our study and for considering this as an alternative is because of the difference in side effect profile between the hormonal therapy options and olaparib. So men a lot of times in this setting are totally asymptomatic from their disease. So the side effects that people can develop are really more related to the drugs that we give rather than the disease at that time point. We obviously didn't compare to standard of care treatment, which would include hormonal therapy, but used this as an opportunity to see if there was efficacy. And that's one of the studies that may be done down the line to compare efficacy to standard of care.

Andrea Miyahira: Okay, thank you. And speaking of side effects, are there any that we would need to be concerned about with using PARP inhibitors earlier in the disease history?

Cathy Marshall: Yeah, so the side effect profile that we saw in our study was similar to what we would expect to see from olaparib. Certainly with PARP inhibitors in general, there's a potential risk for MDS and AML, which we didn't see in our study, but our group and others are also researching to see if we can identify who may be at higher risk for some of these treatment-related complications, and then potentially be able to identify those patients early and help to counsel patients on what that risk might be long term.

Andrea Miyahira: Okay, thanks. And is your team looking for acquired resistance mechanisms such as BRCA reversion mutations?

Cathy Marshall: Yeah, so we're currently working on more of the correlative studies to look to see mechanisms of resistance in those who initially had a disease response and then had progression later on, and then also looking in the other non-BRCA population to see what explains some of those really good responses that we saw in a couple of those patients.

Andrea Miyahira: Okay, thank you. And based on these studies, what do you think should be done next in regards to looking at olaparib in BCR patients?

Cathy Marshall: Yeah, so we're definitely thinking about larger studies for olaparib in the absence of hormonal therapy and also in combination with hormonal therapy and androgen receptor pathway inhibitors, which have been studied later in the disease course. And thinking about how to do those earlier on where, like we mentioned before, efficacy may be higher.

Andrea Miyahira: Okay. Well, thank you so much, Dr. Marshall, for sharing this study with us.

Cathy Marshall: Thanks for having me.