Multidisciplinary Discussions Move the Needle Toward Innovative Prostate Cancer Care

Standardized definitions of biochemical recurrence in prostate cancer can build a comprehensive understanding of the disease and help the field shift away from single-agent regimens and toward combination therapies, such as salvage radiation therapy plus hormonal therapy, according to Michael S. Cookson, MD, MMHC.

“We’[ve been] trying to convert patients with metastatic disease, especially low-volume metastatic disease, into a disease state that is manageable for over a decade,” Cookson said in an interview with OncLive® during the 2023 Prost8 Cancer Conference.

In the interview, Cookson discussed considerations for diagnosing and treating patients with biochemically recurrent prostate cancer and the crucial nature of multidisciplinary collaboration when determining the extent of a patient’s disease and effective treatment options.

Definitions of what constitutes biochemical recurrence in prostate cancer vary between sources. For example, the American Urological Association (AUA) defines biochemical recurrence as a prostate-specific antigen (PSA) value of at least 0.2 ng/mL after radical prostatectomy,¹ whereas the European Association of Urology defines biochemical recurrence as a PSA value of over 0.4 ng/mL after radical prostatectomy.² Cookson explained how these discrepancies are sparking a conversation about creating more consistent definitions that could allow for more widely applicable standards of care.

Cookson is professor and chairman of urology at the University of Oklahoma College of Medicine and chief of Urology at the Stephenson Cancer Center in Oklahoma City.

OncLive®: What key points did you address in your presentation on prostate cancer definition during the Prost8 Cancer Conference session on biochemically recurrent prostate cancer?

Cookson: I focused on a contemporized version of biochemical recurrence and reviewed [current definitions]. AUA and [the Society of Urologic Oncology define] PSA as 0.2 [ng/mL] and rising [after surgery]. The Europeans use 0.4 [ng/mL] and rising after surgery.

[Post-radiation therapy], the radiation oncology literature uses the Phoenix criteria definition [of a PSA increase of at least 2 ng/mL above the post-radiation nadir]. However, some of these patients become biochemically recurrent and possibly metastatic at lower numbers.

[We need to make] definitions because around 2006 and 2007, when we started our localized prostate cancer guidelines, we found over 50 definitions for biochemical recurrence after surgery and almost 100 after radiation. That doesn’t include focal ablative therapies. How do we make comparative assessments in the literature if the starting point is all over the board? That was 1 of the main drivers for establishing some essential ingredients. There are shortcomings, but at least this gives us a point to work from.

How did the perspectives from oncologists, radiologists, and urologists come together to form a complex, multidisciplinary conversation about prostate cancer management?

First, we [discussed] the natural history. While it is almost always a prerequisite [for patients] to have biochemical progression followed by local recurrence, metastatic disease, and possibly death from disease, that doesn’t happen for all patients. The original study [from The Johns Hopkins Medical Institutions] demonstrated that 34% of those patients developed metastatic disease and that there was a long [median] natural history from biochemical recurrence to metastatic disease, 8 years, and then from metastatic disease to death, [a median of] 5 years.

Competing comorbidities, such as the patient’s age, can also [come into play]. For example, a Mayo Clinic series showed about an 85% chance that patients wouldn’t die of their disease at 15 years. These were not all high-risk patients. This was biochemical recurrence in all-comers. Biochemical-only disease is not necessarily a trigger for treatment or a death sentence.

Delving deeper, for surgical patients, the grade of the cancer is important. Patients with early biochemical recurrence, or those who never achieve undetectable disease, are at higher risk of recurrence and require special attention. In radiation, [factors] like doubling times matter. Multivariate models showed rapid doubling time, early recurrence, and high-grade disease to be predictors of higher concern and riskier disease. The absence of those [features] is also associated with a more protracted course.

Artificial intelligence models could incorporate or replace some of our traditional clinical factors. The future is bright for better predictors.

[Regarding] biochemical recurrence after surgery, we need to look at the treatment options. Whether we would consider local or systemic therapy is based on a combination of imaging [tools]. We use PSMA imaging to look for recurrence in those patients, to see if it’s local, metastatic, or oligometastatic.

[For local recurrence], the treatment is usually directed at the pelvis and could [include] combinations of salvage radiation therapy and hormonal therapy. For patients with [local recurrence and] small-volume metastatic disease, we’re in an emerging market of stereotactic body radiation therapy [SBRT] to those small-volume metastatic sites.

The duration of hormonal therapy is debated. We’re also [investigating whether] additional androgen deprivation therapy [ADT] plus a novel hormonal agent can be given for a shorter course compared with the traditional 2 years of therapy. For some patients, a more intensified shorter course plus salvage radiation may be more beneficial than a longer course.

[Regarding] patients progressing on radiation, we’re looking to see where that disease spread. We’re using PSMA PET, also often anatomically looking at the pelvis, and MRI. If we don’t find disease [outside of] the prostate primary, that opens the opportunity for salvage therapy, salvage surgeries, or a variety of salvage ablative therapies. For patients with oligometastatic disease, we discussed hormonal therapy plus SBRT to the small-volume metastases.

What was the most important point of this brainstorming session?

The face of biochemical recurrence is changing. Historically, we relied on PSA, PSA kinetics, and pathology information. That was all we had. Now, we need to move forward with additional PSMA integrated into that. PSMA PET can detect [PSA levels] as low as 0.2 ng/mL. Even in the 0.5 ng/mL range, we’re seeing [findings] we never saw before.

In the absence of PSMA uptake, depending on the PSA kinetics and the absolute number, it may still be appropriate to observe those patients. We’re learning where to direct the therapies. That will open a new frontier.

If a consensus is reached at this meeting, what could this mean for clinical practice?

The sessions were intermixed with questions for the panels. We’re trying to develop the next generation of clinical trials to answer important questions.

Now we have this disruptive innovator, PSMA PET, to try to create a new disease state by more clearly classifying patients. Patients who are negative [for metastatic disease] may truly benefit from local therapy. Patients who are positive for extended disease may do better than what we traditionally knew because they’re classified better and earlier.

We do not have all the answers. [If reached], the consensus from this prostate meeting will be published. However, it won’t be intended as a definitive or prescriptive guideline. It will give information and raise questions regarding where we apply the next investigations.

How did this meeting demonstrate the importance of combination therapies in prostate cancer?

[In metastatic disease], datasets have reported the use of more than traditional ADT. Some of the most recent data, which include [findings from] 2021 and 2022, show we’re not doing a great job of combining therapies.

The combination therapies in metastatic disease are improvements over ADT alone. [We are investigating] doublet therapies with chemotherapy and ADT or perhaps a novel hormonal therapy agent plus ADT. We even have triplet therapy for some patients, particularly those with high-volume disease.

Around 20% of patients are getting a combination therapy [with] a novel hormonal therapy or chemotherapy. We’re not doing them justice. When a patient presents with newly diagnosed metastatic disease, unless there’s a special reason why they can only receive, for example, luteinizing hormone-releasing hormone monotherapy, they should be on combination treatment.

The data have shown survival benefits extending beyond a year in patients, sometimes longer. We’re moving the needle, but we’re not there yet. It starts with considering [patients] for combination therapies, dual therapies, and triplet therapies, not single agents.

How did this meeting contribute to the prostate cancer treatment arena?

This meeting included experts from radiation oncology, medical oncology, urologic oncology, and nuclear medicine. I learned a lot. Getting different disciplines together adds to the learning and helps us take better care of patients.

[We discussed] biochemical recurrence through metastatic to refractory [disease] and neuroendocrine tumors. Hearing perspectives from the different expert areas and investigating ways to develop better treatments for patients is valuable.

What data were you most excited to see presented at the 2023 Genitourinary Cancers Symposium (ASCO GU)?

[There were data about] combination therapies in patients with advanced disease. Historically, drugs were approved [to treat] progressed, castration-resistant [disease in the] second and third lines. [We had a] slow but progressive move to the earlier disease states.

At ASCO GU, combination therapies [were presented], such as PARP inhibitors combined with novel hormonal therapies in first-line castration-resistant disease. Especially in patients with HRR [homologous recombination repair] mutations, we’re seeing a benefit, rather than waiting until they progress.

[These data demonstrated that using 1] single agent [until it fails and then switching to another single agent] doesn’t get us to where we want to be and where our patients need to be. Using combination therapies early is an advancement I’m looking forward to. We’re using drugs [up front] that were historically only used at the tail end.

The next step is to move them into newly diagnosed metastatic disease, and then perhaps oligometastatic disease. Urologists and surgeons [need to] consider neoadjuvant and adjuvant therapies to combine and consolidate with our surgical plans to eradicate the disease. Seeing these combination therapies move forward is exciting.

What ongoing research at Stephenson Cancer Center would you like to highlight?

We’re doing campaigns to reach our target audience: patients at risk for prostate cancer who traditionally don’t come forward. The most recent American Cancer Society statistics showed an increase in patients with newly diagnosed metastatic and advanced prostate cancer. That is a ramification of the anti-screening campaigns that occurred because of controversies surrounding prostate cancer screening. We’re also seeing post-pandemic delays in coming forward.

We’re trying to do early detection and screening for our target audience, which includes [patients with] family histories of lung, colon, breast, and prostate cancer. Additionally, African American men have a disproportionate amount of advanced disease and a more aggressive phenotype. We need to reach them.

We’re developing novel tools like an app that’s more attractive [to our target audience]. We are working on home PSMA screenings, so patients don’t need to come to the clinic [if they don’t want to] pay a cost or if they’re not feeling anything. We’re looking at alternative ways to get their attention and do early detection and screening. Maybe then they’ll come forward and get diagnosed, followed by effective early treatment.

For all we talk about with advanced disease, we’re not curing the cancer. Diagnosing and effectively treating high-grade tumors before they metastasize is our best chance to have patients survive 20-plus years with their disease.

References

• PSA testing for the pretreatment staging and posttreatment management of prostate cancer. Accessed February 21, 2023. https://www.auanet.org/guidelines-and-quality
• EAU - EANM – ESTRO – ESUR – ISUP – SIOG Guidelines on Prostate Cancer. Accessed February 21, 2023. https://d56bochluxqnz.cloudfront.net/documents/full-guideline