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Alternative Endpoints: Results that Potentially Accelerate Phase 3 Clinical Trials in Metastatic Hormone-Sensitive Prostate Cancer
A new PCF-funded study evaluates two clinical outcomes as potential indicators of overall survival that may ultimately help speed treatments to patients

Clinical trials can bring life-extending and potentially curative new treatments to patients with cancer. They play a vital role in determining the safety and efficacy of investigational treatments, generating data which the FDA requires for making decisions on whether a new therapy can be approved and enter widespread clinical practice.

How Clinical Trials Measure Benefit to Patients

Trials are carefully designed in advance to measure a number of “endpoints,” or outcomes, such as: how long on average patients remain alive (overall survival), tumor shrinkage, pain, and quality of life. Some endpoints, especially survival in cancer, generally take months or years to measure, thus clinical trials take several years to complete. All the while, patients may be waiting to gain access to potentially life-prolonging or even life-saving therapies.

To speed up approval of therapies for serious conditions, the FDA allows the use of “intermediate clinical endpoints” that take less time to show results. These intermediate endpoints must first be carefully vetted to show that they are reasonably likely to predict the ultimate endpoint of interest. For example, if it is determined that seeing tumor shrinkage on scans predicts that the patient lives longer, tumor shrinkage – which can be measured much sooner – could be used as an endpoint (instead of overall survival) for FDA approval of a new cancer treatment.

Near-Term Measures Show Promise

Dr. Susan Halabi, PhD
Dr. Susan Halabi, PhD

At the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting this week, Dr. Susan Halabi, PhD, Chief, Division of Biostatistics, and Professor of Biostatistics and Bioinformatics at Duke University School of Medicine, presented results of a study assessing two shorter-term endpoints in trials of patients with metastatic hormone-sensitive prostate cancer (mHSPC). The team analyzed data on more than 8,500 patients with mHSPC who were enrolled in trials comparing hormone therapy + docetaxel vs. hormone therapy alone.

The researchers evaluated whether radiographic progression-free survival (rPFS; defined as time to disease progression on bone or CT scans or death) and clinical progression-free survival (cPFS; defined as time to radiographic progression, symptoms, initiation of new treatment, or death) are correlated with overall survival.

The analysis showed that both rPFS and cPFS met a pre-defined threshold for correlation to be considered as potential intermediate endpoints (in lieu of overall survival) in mHSPC phase 3 clinical trials. The investigators plan to validate these results by using data from recent clinical trials to understand whether these outcomes are valid surrogates in contemporary patients.

“The readout from phase 3 clinical trials in men with metastatic hormone sensitive prostate cancer can take a decade if survival is used as the primary outcome,” notes Halabi. “This analysis highlights the importance of identifying intermediate markers of survival and underscores the maximal use of data collected from global clinical trials. While the results are promising, the goal is to go one step further and demonstrate the benefit of using these valid intermediate outcomes in contemporary treatments to the U.S. Food and Drug Administration and other regulatory agencies.“

“As it stands, it has massive implications for future prostate cancer trials – saving time, money, and, most importantly, lives – by helping them prove a treatment’s effectiveness sooner. We hope that this is just the first step, and we can find ways to get treatments to men even more quickly in the future.”

The project was initially funded by a 2018 Movember Foundation – PCF VAlor Challenge Award.

What this could mean for patients: In a clinical trial, other measures (radiographic and clinical progression-free survival) could be measured much sooner than overall survival results, which can take years. This could shorten the time to clinical trial completion and, ultimately, drug approval and patient treatment – without sacrificing accuracy in measuring clinical benefit of novel drugs to patients.