Reflecting on Advances Made in High-Risk, Low-Grade Prostate Cancer Management

Howard I. Scher, MD

With a reflection on the past paradigm-changing studies done in advanced prostate cancer, Howard I. Scher, MD, emphasized that the field needs to shift focus to earlier-stage settings, spotlighting intriguing clinical trials and research efforts that are already underway.

Scher, who serves as the head of the Biomarker Development Program and the D. Wayne Calloway Chair in Urologic Oncology at Memorial Sloan Kettering Cancer Center, in New York, New York, delivered the Giants of Cancer Care^® keynote address during the 2023 CFS^®, an event hosted by Physicians’ Education Resource, LLC.¹

He underscored that a new treatment paradigm is needed for drug development in patients with earlier-stage prostate cancer. “With the rapidly increasing number of therapies that are in the pipeline, in development and approved, there are simply too many agents and combinations to test and too few patients in whom to study them.”

Prostate-specific membrane antigen (PSMA) imaging is redefining metastatic disease, he added, and leaders in the landscape need to urgently accelerate drug development, define objective criteria to rank and prioritize treatment approaches that are worthy of future phase 3 investigations, and “reduce the resources needed to do so.” This includes new ways of measuring success in clinical trials, he said.

Throughout his presentation, he shed light on various research programs he has led or has been heavily involved with that have helped change the course of prostate cancer treatment over the years.

Prostate Cancer Treatment: It Has Come a Long Way

Before there was PSA testing, there was limited CT; bone scans were assessed on plain films. In the early clinical trial realm, such studies focused on changes in measurable disease; however, there was no consistency in design, assessment, and reporting, Scher said.

“We reached the point that stress [of PSA returning or rising] was so hard on families, on patients, and on staff, that we actually started working with a psychiatrist, who was extremely helpful in helping them deal with these new issues that were coming up.”

The Prostate Cancer Foundation Is Born

In 1993, CapCURE was founded by Michael Milkin, MD. The name was later changed to Prostate Cancer Foundation (PCF), which Scher announced is in its 30th year and was created with a very simple mantra: “Don’t tell me about the problem. Just tell me what you are going to do about it.”

With the foundation, the prostate cancer community expanded with multiple disciplines, as well as research support across several areas of the disease. “Enthusiasm was high, but execution was challenging for a range of reasons, largely administrative.”

Becoming More Precise

The evolved understanding of prostate cancer biology led to improved eligibility and outcomes reporting recommendations from the Prostate-Specific Antigen Working Group.² They outlined guidelines for trial eligibility based on PSA kinetics that allowed for the prediction of which patients require treatment based on their risk for developing metastases, worsening symptoms, or death. Additionally, the research showed that an intervention alters the natural history of prostate cancer and can be described based on PSA changes.

“At each stage of development, only agents with sufficient activity should be moved forward,” Scher said.

The need to tailor treatments and make further adjustments to prostate cancer practice cascaded into clinical trial end points. “The manifestations of prostate cancer do not lend themselves to the ‘packaging’ assessments of treatment effects into the RECIST criteria response categories—changes in measurable disease,” Scher said. He highlighted research indicating that 43.5% of patients with metastatic castration-resistant prostate cancer had a measurable target lesion greater than 2 cm vs 16% of those with noncastration-resistant disease, and 84.4% of this was in the lymph nodes.³

Scher discussed the importance of improved imaging, especially in prostate cancer. For example, a master protocol for fluorodeoxyglucose positron emission tomography (FDG-PET) was created to improve bone imaging and other areas of disease in the body. The FDG-PET is still in use today to test new tracers, Scher noted.

The Start of the PCCTC and Novel Research Efforts

In 2005, PCF and the US Department of Dense Prostate Cancer Research Program launched the Prostate Cancer Clinical Trials Consortium (PCCTC), which was created to “foster a culture of transparent projects with co-development between investigators, research sites, and industry partners.” This was then established as an independent entity in 2014; PCCTC, LLC, was known as a multicenter clinical research organization focused on novel research in prostate cancer.

The mission of the PCCTC is “to design, implement, and complete hypothesis-driven trials of novel agents and combinations that could prolong the lives of patients with prostate cancer.” Scher is chairman of its scientific oversight committee.

“What was really impressive was how everybody was coming together and trying to think of ways to do things better based on advances in technology so that our patients’ outcomes were improved,” Scher said.

Today, the PCCTC comprises 112 participating clinical research sites worldwide. It is also expanding to reach other entities, such as the FDA, Stand Up to Cancer, and the National Cancer Institute, as well as industry, patient, and research advocacy groups, among others.

This has inspired a multitude of efforts in the space, including research demonstrating that PI3K, androgen receptor, and DNA damage repair (DDR) pathways are the most frequently altered in the tumor vs BRCA2, which is most frequently altered in the germline.⁴

“Being able to do this enables questions to be answered very quickly and effective drugs to get to patients faster,” Scher said of the PCCTC.

Additionally, from its inception through October 2023, the PCCTC has accrued 13,923 patients to 268 PCCTC trials, 16.4% of whom are from disproportionately affected populations. Overall, their studies account for more than 22% of active, early-phase treatment-driven US clinical trials.

Prostate Cancer Working Group 2 is another organization with a mission to bolster the prostate cancer treatment arsenal, with accomplishments such as the following:⁵

1. Authenticating disease progression prior to treatment initiation
2. Abandoning global tumor response reporting based solely on RECIST v1.1 criteria in favor of reporting changes in each disease manifestation separately.
3. A 2+2 rule that distinguishes bone scan flares from actual disease progression is to be used as a bone scan progression biomarker in phase 3 registrational studies.
4. Ensuring drugs are not stopped prematurely based on unfavorable changes in a disease manifestation that are insignificant from a clinical standpoint.

Another PCF-conducted clinical trial is MetaCURE (NCT03436654), which is a master platform phase 2 trial for patients with newly diagnosed, very–high-risk localized, or low-volume metastatic disease or biochemical recurrence. Investigators are evaluating whether or not selecting AR-driven therapy prior to surgery can shrink tumors as much as possible to prevent recurrence. Patients would receive androgen deprivation therapy monthly or every 3 months; the study drugs are abiraterone acetate (Zytiga), apalutamide (Erleada), and prednisone.

Finally, Scher pointed to a new clinical trial platform in development called ADAPPT, which simultaneously evaluates investigational agents and interventions for patients with very–high-risk localized and low-volume mCRPC. The platform will be overseen by a master clinical trial protocol and new experimental arms can be added at any time.

“It’s been quite a ride now over 40 years, [being able] to see all these changes [in the paradigm] and patients who have been with you. [Survival has] more than doubled and is in the double digits,” Scher concluded. “It’s really a thrill considering where things were when I first started.”

Editor's Note: Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.

References

1. Scher HI. Giants of Cancer Care lecture: changing paradigms to improve prostate cancer patient outcomes. Presented at: 2023 CFS^®; November 8-10, 2023; New York, NY.
2. Scher HI, Eisenberger M, D’Amico AV, et al. Eligibility and outcomes reporting guidelines for clinical trials for patients in the state of a rising prostate-specific antigen: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol. 2004;22(3):537-556. doi:10.1200/JCO.2004.07.099
3. Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: ‘‘RECIST’’ing a step backwards. Clin Cancer Res. 2005;11(14):5223-5232. doi:10.1158/1078-0432.CCR-05-0109
4. Pritchard C, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Eng J Med. 2016;375(5):443-453. doi:10.1056/NEJMoa1603144
5. Scher HI, Halabi S, Tannock I, at al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26(7):1148-1159. doi:10.1200/JCO.2007.12.4487