NePtune Trial: Evaluating Neoadjuvant PARP Inhibition in BRCA-Mutated Prostate Cancer - Rana McKay

March 26, 2024

Rana McKay discusses the NePtune study, investigating PARP inhibitors as a neoadjuvant treatment for prostate cancer patients with BRCA1/2 mutations. This study, inspired by the success of PARP inhibitors in metastatic settings and neoadjuvant successes in other cancers, aims to address the aggressive nature of BRCA-mutated prostate cancer earlier in the disease course. With a multi-institutional approach, the study targets a select patient population for six months of neoadjuvant therapy with olaparib and ADT, followed by radical prostatectomy, hoping to replicate the profound pathologic responses seen in breast cancer research. This trial could significantly impact the management of high-risk prostate cancer patients, underscoring the importance of collaborative efforts in advancing treatment paradigms.


Rana McKay, MD, Medical Oncologist, Associate Professor of Medicine, UC San Diego School of Medicine, San Diego, CA

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA

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Alicia Morgans: Hi. I am so excited to be here today with Dr. Rana McKay, where we're talking about a poster presentation for a trials in progress that she gave at GU ASCO 2024. This is a study investigating the use of PARP inhibitors in a neoadjuvant strategy prior to prostatectomy for patients with prostate cancer. Thank you so much for being here with me today, Dr. McKay.

Rana McKay: Oh, thanks so much for having me. It's exciting to get to talk to you about the NePtune study.

Alicia Morgans: Wonderful. Well, tell me, how did you come up with this idea? I know neoadjuvant strategies have been a passion of yours for many years, but why PARP? Which patients? Where did this idea come from?

Rana McKay: Oh, very good question. So we know that patients who have BRCA1/2 mutations and prostate cancer have more aggressive disease, have an increased risk of disease recurrence and metastasis development. Neoadjuvant treatment is a standard of care for many malignancies, including breast cancer, rectal cancer, and other types of cancers. We've conducted a series of neoadjuvant hormonal therapy trials prior to surgery in men with high-risk disease, demonstrating that, actually, a subset of patients do have favorable pathologic responses with a pathologic complete response, or minimal residual disease after receiving neoadjuvant therapy. And we've also been able to follow those patients over time and actually demonstrated that in the subset of patients who do have a favorable pathologic response, the likelihood of those patients recurring is very low, and they tend to have good long-term favorable outcomes.

We know ADT is a highly effective therapy for patients with prostate cancer and is the backbone of systemic therapy for patients with prostate cancer. But people who have BRCA alterations can have resistance to hormonal therapy. And patients who have BRCA1/2 mutated prostate cancer, there have been several studies conducted in the mCRPC setting that have demonstrated those individuals live longer when they receive a PARP inhibitor. And so the paradigm here is thinking, okay, we know these patients have more aggressive disease. We know we've demonstrated that in a subset of patients they can actually achieve good outcomes with neoadjuvant therapy. In this study, we're basically asking the question of why wait until patients get metastatic disease? Why not use the PARP inhibitor upfront in a selected population where we know that this therapy has efficacy?

So this trial is designed for those patients that have unfavorable intermediate or high-risk prostate cancer, that have a germline or somatic BRCA1/2 alteration. Patients will receive six months of neoadjuvant therapy with olaparib and ADT, followed by a radical prostatectomy, and they'll be very closely monitored prior to surgery, and when they're on their hormonal treatment and olaparib, and also after their radical prostatectomy, with serial PSA and imaging at select time points.

So it's really interesting because I think if we look at the breast cancer literature, studies of neoadjuvant PARP inhibitors in selected patients with localized or locally advanced breast cancer actually demonstrated really profound pathologic responses. In a study of talazoparib in this context, the pathologic complete response rate was 50% in this population. And so, this is definitely an area where we can potentially make a huge impact.

Based on the results of the OlympiA study, which was a study of adjuvant olaparib in BRCA1/2 mutated patients with localized breast cancer, that study was positive. There's the FDA approval of olaparib in the adjuvant setting for women with breast cancer. So we're about a decade behind in prostate cancer. And hopefully, this will be an initial foray into looking at PARP inhibition in the localized setting, targeting a very select patient population.

Alicia Morgans: Great. So given that it is such a select population, it can be hard, certainly, to do this at a single institution. Is this a multi-institutional study? And where else, more or less, are you open, if it is?

Rana McKay: Very good. Yeah, it's definitely a multi-institutional study that's being coordinated through HCRN. The study is open at UCSD, MSKCC, and their adjoining satellites, UPenn, Johns Hopkins, and we're working on onboarding Cornell and one additional site. And so, this will be open across the US.

It's a really important study, small sample size, not a lot of patients to enroll, so 32 for 30 evaluable patients. But I think the study is going to require large screening efforts. So NCCN guidelines have been updated for those high-risk patients. Definitely, recommend germline genetic testing for those individuals. And so, it's going to take screening 100 patients to find four or five individuals that could potentially be eligible.

Alicia Morgans: Great. Well, if anyone can do it, I'm sure you and your team can. So I think we're really very much looking forward to that. And this study is actively enrolling at this time, as I understand, and I'm sure is advertised on

Rana McKay: That's correct. It's actively open and enrolling. And right now, the four sites that are actually open are UCSD, MSKCC, Penn, and Hopkins.

Alicia Morgans: Fantastic. So we'll make sure to put a link to that page, so that patients and clinicians who are interested can get more information. But anything else you want to share as we wrap up?

Rana McKay: No. I think this is definitely a study where we, as a community, need to come together and ensure that we're doing the screening for the individuals, work collaboratively between medical oncology and our urology colleagues. And it's going to be a really critically important study for us to make a dent in the natural history of BRCA mutated prostate cancer.

Alicia Morgans: Absolutely. And we know that PARP inhibitors can be so effective in prostate cancer. Lots of data are coming out with PARPs and PARP combinations that really, really just kind of drive this home. And so, we really do look forward to you continuing enrollment, completing the study, and sharing the results with us in the future. Thank you so much for your time and your expertise.

Rana McKay: Thank you so much.