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Jason Efstathiou: Hello, I'm Dr. Jason Efstathiou, radiation oncologist at Massachusetts General Hospital in Boston.

Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute, also in Boston.

Jason Efstathiou: On behalf of both of us and our co-authors, it's our pleasure to present a commentary titled Novel Hormone Therapy and Coordination of Care in High-Risk Biochemically Recurrent Prostate Cancer - Beyond the Abstract. This commentary is based on a recently published review on management of biochemical recurrence in cancer treatment reviews. This commentary was funded by Pfizer and Astellas Pharma, the co-developers of enzalutamide. Medical writing and editorial assistance were funded by Pfizer and Astellas. Author disclosures are included in the published manuscript.

Alicia Morgans: Great. So Jason, I think it'd be wonderful if we could take a few minutes to just lay out the problem, first with an initial discussion of what biochemical recurrence is. How common is it? Why is it something we should worry about?

Jason Efstathiou: It's a great question, Alicia. So biochemical recurrence or BCR is defined as rising PSA levels after definitive therapy such as a radical prostatectomy or radiotherapy without evidence of metastasis by conventional imaging. So what's conventional imaging? Bone scan, CT scan, et cetera. About 20 to 50% of patients with prostate cancer will experience BCR within 10 years of definitive therapy. That's a pretty high number. And patients with high risk BCR have an increased likelihood of distant metastasis, prostate cancer-specific mortality, and overall mortality. The definition of high risk BCR has continued to evolve as new clinical evidence has become available. And managing high risk BCR is challenging due to disease heterogeneity. So therefore we as clinicians really need to use a risk stratification strategy when managing these patients. In addition, the landscape of treatments and diagnostic and imaging modalities for high risk BCR is highly complex and rapidly evolving. Multidisciplinary care and treatments based on optimizing risk stratification provide potential benefits and opportunities when addressing these challenges of BCR management. So, Alicia, could you tell us a little more about risk factors for BCR and how we might risk stratify patients?

Alicia Morgans: Absolutely. And really to emphasize risk stratification is so important in biochemical recurrence because patients with low risk biochemical recurrence may live for years and years with a measurable PSA, but with no evidence of metastatic disease on scans and they may never have a complication of their cancer. And so these are patients that we might decide not to treat because the treatment may be worse than the disease. The things that we use to risk stratify in biochemical recurrence include things like a short interval to developing biochemical failure, a high Gleason score greater than eight, and a short PSA doubling time. And I think the field has really focused in on this short PSA doubling time as one of the most important factors associated with the risk of recurrent disease in the development of metastatic disease. And we think usually about a PSA doubling time of 10 months or so or less as being that highest risk subgroup.

I think there's also interest in the field for us to develop genomic classifiers and other ways to use molecular information to understand which patients may be at highest risk, but this is not yet ready for prime time and is not yet something that we use in clinic at this point in time. And the other thing that's been a more recent advance in our understanding of biochemical recurrence risk stratification has been the use of PSMA PET, with patients having PSMA PET positive disease, having a poor prognosis and certainly more advanced biochemical recurrence than those patients who have a PSMA PET that is negative. And this is definitely an area of active investigation.

Jason Efstathiou: Excellent. That's very interesting. And you alluded to systemic therapies for the treatment of BCR. I know this is also a rapidly evolving area. Can you tell us a little bit more about what type of treatments there are for BCR?

Alicia Morgans: Of course. I think traditionally our age-old treatment with androgen deprivation therapy is a key first line therapy for biochemical recurrence. But again, we work really hard in clinic to make sure that we're primarily selecting those patients who have biochemical recurrence that's worth treating when we're using androgen deprivation therapy. The studies that have been done with ADT have not necessarily shown that ADT alone meaningfully changes the trajectory of the patient's disease progression. So it may not prevent metastatic disease and death from prostate cancer, which is a main goal and priority. Some of the more recent data that really does meaningfully change the disease trajectory is the EMBARK trial, which was a phase three registration trial that demonstrated that ADT in combination with enzalutamide, and actually even enzalutamide on its own, can prolong metastasis-free survival versus leuprolide and ADT alone in patients with high risk biochemical recurrence.

This was the first time we've really seen such a meaningful change in disease and I think was a really important advance in the field. There is active investigation in whether we can use other approaches to treat this disease as well, and a lot of that is actually really revolving around PSMA PET targeted therapies or therapies that we might use in combination with metastasis-directed therapy, radiation techniques. So active investigation ongoing here as well, and I really think that this is an area that we need to keep an eye on as we move forward. So I wonder, Jason, you're a radiation oncologist. I'm a medical oncologist. How does multidisciplinary care come into play for biochemical recurrence?

Jason Efstathiou: Yeah, it's so important. I am a huge believer in multidisciplinary care, and I think the treatment combinations that you discussed just now represent excellent examples of the need for multidisciplinary care because they really leverage the combined expertise of oncologists, that surgical medical radiation and radiologists. You've talked about the emergence and importance of PET imaging, for example. But in multidisciplinary care, multiple experts work together to assist in stratifying individualized risk for the patient based on standard clinical pathologic parameters, but also next generation imaging and perhaps even molecular biomarker analysis. And this team-based approach incorporates, as I mentioned, urologists, medical oncologists, radiation oncologists, but also other healthcare professionals, maybe pharmacists, nurse practitioners, and others. And there are a number of potential benefits of multidisciplinary care that have been defined and looked at. And they include things such as increased patient engagement and satisfaction of their care. Reduced risk of physician bias.

We all know we're biased towards perhaps our expertise and our particular specialty, but if we work together, we reduce that risk. Increased cross-referral. You alluded to radiation potentially playing a role in certain cases of BCR. Increased patient participation in clinical trials, absolutely. There's more awareness of what trials might be available if we're seeing these patients together and working together. And by the way, there's much more opportunity for us all to collaborate in research as well, as providers. There's also increased adherence to treatment guidelines and enhanced shared decision making that's really patient informed. So I think a lot of real measurable benefits of multidisciplinary care, and when combined these factors could even improve patient survival outcomes. So indeed there is evidence that multidisciplinary care clinics and multidisciplinary care referrals can be beneficial in prostate cancer, but still the evidence of that kind of care implemented for the treatment of patients with high risk BCR is rare and I think remains an area that's an unmet need and an area of opportunity. So, Alicia, put it all together for us. We've heard about the definition of BCR, we've heard about risk stratification, we've heard about systemic therapies and emerging therapies. We've heard about the importance of multidisciplinary care in this setting. How would you put it all together?

Alicia Morgans: Well, thank you. I think the first thing we have to recognize here is that biochemical recurrence is not as uncommon as we all wish it should be if we could cure more patients from the get-go. It absolutely happens and when it does, we need to make sure that we're using a risk stratified approach to identify those patients at the highest risk of having a complication from their cancer or dying from their disease. And in those patients, therapeutic advances have been made that help us meaningfully change the trajectory of disease, including that data that we have from the EMBARK trial, which really helped us understand that enzalutamide and ADT, or enzalutamide on its own can prolong metastasis free survival versus leuprolide in this high risk biochemical population. And I think as we ultimately implement these findings in our practices, we're going to be using newer technologies, we're going to be using PET scans, we're going to have to rely on the multidisciplinary approach to work together to really get the best treatments for our patients, whether they're systemic treatments or whether over time they may be more multidisciplinary type therapies, including radiation type approaches. And ultimately, as we do our best to work together as teams, we will be able to help improve the outcomes for our patients with biochemical recurrence.

Jason Efstathiou: Great. Thanks so much, Alicia. And obviously there's huge opportunity and high risk BCR, and we thank all the listeners for watching this video.

Alicia Morgans: Thank you.