Immunotherapy and PARP Inhibitors in Biochemical Recurrent Prostate Cancer - Alexandra Sokolova
August 7, 2022
Alexandra Sokolova, MD, Assistant Professor of Medicine, Division of Hematology/Medical Oncology, School of Medicine, Oregon Health and Sciences University, Portland, Oregon
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
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Alicia Morgans: Hi, I'm so excited to be at ASCO 2022, where I have the opportunity to speak with Dr. Alexandra Sokolova about her work in biochemical recurrence. Thank you so much for being here.
Alexandra Sokolova: Thank you for having me here today.
Alicia Morgans: Wonderful. Well, I wanted to speak with you about a trial that you have, with your team at OHSU, in progress. Thinking about patients with biochemical recurrence, it's an area that remains a little undefined in terms of how we best care for patients. And this is a really innovative trial. You presented it as a trial in progress at ASCO. Tell us a little bit about the study and how you chose the patients to be involved.
Alexandra Sokolova: Absolutely. So, the study focuses on biochemical recurrent prostate cancer. So patients who had definitive radiation, or surgery, as definitive treatment for localized disease, but developed by chemical recurrence. And unfortunately, that happens in up to 30% of people who get definitive treatment. And the timing of treatment, and the treatment itself, is somewhat controversial in this disease space. Intermittent energy deprivation therapy is an option. Observation is an option. There is really no overall survival, benefit, kind of in high-quality data, proven in this space.
And so, our study focuses on a higher risk of this population, patients who have a shorter PSA doubling time, less than 10 months. So those at a high risk of developing metastasis and actually having worse outcomes. And we use targeted drugs for molecular selected population. We use durvalumab, which is immune checkpoint inhibitor. And olaparib, which is a PARP inhibitor, in patients who are predicted to have high neoantigen load.
And three cohorts with predicted high neoantigen load will be included in the study. The first one is mismatch repair efficiency, which is kind of our bonafide population that has shown the best response to immunotherapy in the past. And we know that they have a high neoantigen, and they're more likely to respond to immune checkpoint inhibitors.
The second cohort is patients with biallelic CDK12 mutations. So this is a little bit of a newer subset that was defined in prostate cancer, which is characterized with genomic instability, a lot of fusions, and kind of a very signified signature with tandem duplications. Which results in a lot of new neoantigens, predicted to have a high response to immunotherapy.
And a third cohort is homologous recombination deficiency. In homologous recombination deficiency, there are two thoughts of potentially using the immune checkpoint inhibitor. First, the neoantigen load is increased in homologous recombination deficiency, because DNA repair is impaired, there are a lot of mutations, new proteins presented. And then second of all in preclinical models, there is data suggesting that PD-1/PD-L1 expression is increased in tumors that have homologous recombination deficiency. So that's another rationale to use those drugs in this patient population.
So, there are going to be three cohorts that are going to be analyzed separately in use of those combination drugs of durvalumab and olaparib.
So why is olaparib there? There is twofold reasoning to adding olaparib to durvalumab. On one hand, PARP inhibitors, they impair DNA repair. So there is more mutations, new proteins, higher neoantigen load. On the other hand, they also activate some immune pathways, such as a STING pathway. So they increase this immune response of the patient to the tumor.
And so we hypothesize, that by using these two targeted drugs in synergy, in this highly selected patient population, we hopefully can cause, kind of a deeper remissions and postpone the need for androgen deprivation therapy.
So the goal of this trial is, choose those patients that are at high risk of developing metastasis, and have worst outcomes of prostate cancer. Use those target drugs early on, without androgen deprivation therapy, will hopefully improve the quality of life and survival.
Alicia Morgans: I think that's fantastic. This approach is really, really interesting, and I love that you have your three cohorts, and you've designed the analysis around those cohorts. I wonder, are you using androgen deprivation therapy as a backbone with this combination, or is this given on its own to spare patients from castration?
Alexandra Sokolova: The way we design this study is without ADT, so the goal is to spare them castration. And these drugs have their side effects as well, but we're using them for a short period of time, a total of six months. So, the goal is, by giving those drugs for a limited, short amount of time, to avoid the need for long-term ADT use in the future.
Alicia Morgans: And that's fantastic. I think patients will find that really appealing. Now I wonder, what are the endpoints that you're looking for? And of course, I assume you're looking for these independently within each of the cohorts.
Alexandra Sokolova: You're absolutely correct, each cohort will be analyzed independently. And our primary endpoint is undetectable PCa at 12 months. We'll also be looking at other kinds of progression-free endpoints, so radiographic progression-free survival, event-free survival, [inaudible 00:05:14] safe-free survival. We're looking at adverse events, and the quality of life managed for those patients.
Alicia Morgans: Wonderful. So, if patients, or if clinicians are excited to potentially refer their patients, or get them involved in this study, can you tell us, is this only open at OHSU? And if they somehow get to OHSU, how do they contact, how do they reach out to the team, to get involved?
Alexandra Sokolova: The study is currently open at two sites, University of Washington, Seattle, at OHSU in Portland. Patients can come and get treated, and be seen at both of those sites. For OHSU's site, we actually have a kind of clinical trial phone number and email, that patients can send a message to and get in touch with the research team, and getting to be screened for the study, and enrolled if they're eligible.
Alicia Morgans: Wonderful. And we'll make sure we put the ClinicalTrials.gov NCT number, so that patients can also look it up on the internet, just to monitor along the way and continue to hear how things go.
So I look forward to hearing from you in the next couple of years, how this has gone and how we can move forward. Hopefully, with positive data suggesting a good safety profile, and maybe some early efficacy, so we can think about a phase two, or even further. Thank you so much for your time and congratulations on this study.
Alexandra Sokolova: Thank you.