Phase II A-DREAM Trial: 41% of Exceptional Responders Remain Off ADT at 18 Months in Metastatic Prostate Cancer
核心洞察
The phase II A-DREAM/Alliance A032101 trial found that 41% of metastatic hormone-sensitive prostate cancer (搜索) patients with exceptional response to ARPIs remained off androgen deprivation therapy (搜索) at 18 months with testosterone recovery.
After a median follow-up of 26.9 months post-treatment interruption, 38.5% of patients still had not needed to resume any treatment, including those with high-volume disease.
Only one of four deaths during follow-up was attributed to prostate cancer, suggesting no negative cancer-related outcomes from the treatment break.
A planned treatment interruption strategy for metastatic hormone-sensitive prostate cancer (搜索) (mHSPC) patients who achieve exceptional responses to androgen receptor pathway inhibitors (搜索) (ARPIs) may allow a substantial proportion to enjoy prolonged treatment-free intervals with testosterone recovery, according to findings from the phase II A-DREAM/Alliance A032101 trial presented at the 2026 ASCO Annual Meeting.
Atish Choudhury, MD, PhD, of Dana-Farber Cancer Institute, presented results showing that 41% of patients who stopped treatment met the primary endpoint — remaining off therapy at 18 months with testosterone recovery and without needing to resume androgen deprivation therapy (搜索) (ADT).
Study Rationale and Design
The trial was motivated by a straightforward clinical observation: many men with metastatic prostate cancer achieve undetectable PSA levels on ARPI plus ADT combinations, yet current treatment paradigms require indefinite continuation of therapy, subjecting patients to ongoing toxicities and costs.
"What we're observing in our practice is that there are many men whose PSA level, which is a measure of their cancer activity, goes to undetectable levels on these medicines. And then you're keeping them on continuously, kind of forever, for the rest of their life," Choudhury explained.
The investigators designed a study enrolling patients whose PSA fell below 0.2 ng/mL at the 18- to 24-month treatment time point. Treatment was then stopped, and patients were monitored with PSA and testosterone checks every 3 months, imaging every 6 months, and quality-of-life assessments every 6 months. The trial enrolled 78 patients, exceeding the planned 75.
Key Findings
The primary endpoint — the percentage of patients reaching 18 months after treatment cessation with testosterone recovery and without requiring treatment resumption — was 41%, surpassing the prespecified threshold of 30% that investigators deemed clinically interesting for further study.
With extended follow-up, the results appeared even more durable. "As we've been following these men a median 26.9 months after stopping treatment, actually 38.5% of the patients, even at that later time point, haven't needed to resume any treatment whatsoever, which is probably a higher number than what most people would have expected," Choudhury noted. This durability was observed despite approximately 35% of enrolled patients having high-volume disease at baseline.
Safety Signals
Among the four deaths recorded during follow-up, only one was attributed to prostate cancer. The remaining three deaths resulted from unrelated causes: myelodysplastic syndrome, influenza, and myocardial infarction. "So there's no obvious evidence from our study that there's some negative cancer-related outcome by taking this treatment break," Choudhury stated.
Clinical Implications
Matthew R. Zibelman, MD, associate professor and director of genitourinary clinical research at Fox Chase Cancer Center, who was not directly involved in the trial, commented on the findings: "While I think larger trials and more data may be necessary to really help us understand the exact frame and guardrails around this type of treatment, I think this does give us leeway to now talk with some of our patients about this possibility and consider breaks in therapy, which I think all will be interested in."
Choudhury offered practical guidance for clinicians: "Even in the absence of real randomized phase 3 data, if you have a patient who's struggling with side effects from treatment, if they're an exceptional responder, they could probably safely take a break and probably, if you resume the treatment, still have activity against the cancer and probably have a very low likelihood of dying of prostate cancer."
Future Directions
The investigators are now pursuing retrospective molecular analyses to identify which patients are most likely to experience prolonged treatment-free intervals. Choudhury acknowledged the challenge of designing future trials, questioning whether continuous treatment should remain the default comparator arm given the toxicities associated with indefinite therapy.
"What we're trying to learn now, based on retrospective studies of this study incorporating some molecular analysis as well, is who are the patients who can have these very prolonged treatment-free intervals? And can we design trials to more smartly identify those patients and more smartly potentially stop treatment even earlier or in a larger subset of patients or maybe a smaller subset of patients?" Choudhury said.