Among the studies presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, one of the most discussed and closely scrutinized was PROTEUS, a Phase III trial in prostate cancer. What made the study particularly intriguing was that it was not a failed trial. On the contrary, it was a clear statistical success. Pathological responses improved, and both metastasis-free survival (MFS) and event-free survival (EFS) were significantly prolonged. Yet despite these positive results, a different question dominated conversations among researchers at ASCO:

“Can we trust pCR in prostate cancer as well?”

This question extends far beyond prostate cancer. As immunotherapies and targeted therapies rapidly expand into the perioperative setting, it has become one of the central questions in oncology drug development as a whole.

How Did pCR Become an Important Endpoint?

Pathologic complete response (pCR) refers to the complete disappearance of invasive cancer cells in the surgical specimen following neoadjuvant treatment. The concept is straightforward: if no cancer cells can be detected under the microscope after treatment, patients should theoretically experience better long-term outcomes.

Indeed, this correlation has long been observed at the individual patient level. Patients who achieve pCR generally have lower recurrence rates and better survival outcomes than those who do not. However, predicting an individual patient's prognosis is fundamentally different from serving as a surrogate endpoint in clinical trials. To qualify as a true surrogate endpoint, it is not enough that patients achieving pCR fare better; there must also be evidence that treatment-induced increases in pCR translate into meaningful reductions in recurrence and improvements in survival.

Breast Cancer Opened the Era of pCR

Breast cancer is the disease setting in which pCR has been most successfully established. In particular, strong associations between pCR and long-term outcomes have been repeatedly demonstrated in HER2-positive breast cancer and triple-negative breast cancer (TNBC). Studies such as NeoSphere showed that increases in pCR were accompanied by genuine clinical benefits, leading the U.S. Food and Drug Administration (FDA) in 2014 to recognize pCR as a surrogate endpoint for accelerated approval in breast cancer drug development.

This fundamentally changed the paradigm of oncology drug development. Rather than waiting years for disease-free survival (DFS) or overall survival (OS) results, developers could evaluate efficacy based on neoadjuvant treatment outcomes alone.

However, the success of pCR in breast cancer did not automatically extend to other tumor types. Neoadjuvant strategies have been investigated in lung, esophageal, bladder, and rectal cancers, among others, but pCR rates were often low, and the relationship between pCR improvements and survival outcomes was not always clear. For many years, pCR was therefore regarded largely as a “breast cancer endpoint.”

The emergence of immunotherapy began to change that perception. Trials such as CheckMate-816, KEYNOTE-671, and AEGEAN demonstrated that neoadjuvant immunotherapy could induce substantial pathological responses and, in some cancers, lead to improvements in EFS. As a result, pCR returned to center stage in oncology drug development.

The Question Raised by PROTEUS

Against this backdrop, PROTEUS was designed to evaluate whether improved pathological responses in prostate cancer could translate into meaningful clinical benefit.

This global Phase III trial enrolled 2,109 patients with high-risk or locally advanced non-metastatic prostate cancer. All patients underwent radical prostatectomy and received long-term androgen deprivation therapy (ADT), with either apalutamide or placebo added in both the neoadjuvant and adjuvant settings.

The co-primary endpoints were the rate of achieving pCR or minimal residual disease (MRD) and metastasis-free survival (MFS).

The results were clearly positive. The pCR/MRD rate reached 8.9%, approximately nine times higher than the 1.0% observed in the control arm. MFS was also significantly improved (HR 0.80), and EFS increased from 38.4 months to 57.1 months.

Importantly, PROTEUS was not a negative trial. It met its co-primary endpoint of MFS and delivered a statistically significant benefit. The treatment reduced the risk of metastatic progression and delayed the need for additional systemic therapy or radiotherapy, providing meaningful clinical benefit for patients with high-risk disease.

Nevertheless, discussions at ASCO focused less on the positive results themselves and more on how those results should be interpreted.

The first point of debate concerned the control arm. To preserve the double-blind design, investigators selected ADT alone as the comparator. However, some experts argued that this choice may not fully reflect the range of standard treatment strategies currently used in clinical practice.

The second issue involved MFS. While MFS has been accepted as a surrogate endpoint for overall survival in studies based on conventional imaging, it remains uncertain whether it retains the same significance in the era of PSMA PET-CT, which is being adopted rapidly worldwide.

The most intriguing debate, however, centered on pCR itself.

Unlike breast cancer or lung cancer, prostate cancer is characterized by a much longer natural history and distinct tumor biology. Consequently, whether an increase in pCR alone can be accepted as an established surrogate for long-term survival remains open to question. PROTEUS demonstrated the potential relevance of pCR in prostate cancer, but it did not definitively establish pCR as a surrogate endpoint on par with its role in breast cancer.

In that sense, the most important contribution of PROTEUS may not have been the answers it provided, but the question it left behind. Whether pCR can become a validated surrogate endpoint in prostate cancer remains unresolved—and it is a question that future studies will need to answer.

“pCR Is Only One Part of MRD”

The more important message emerging from PROTEUS may be the concept of minimal residual disease (MRD).

Many people think of pCR as synonymous with MRD, but strictly speaking, pCR is closer to pathologic MRD assessed through surgical specimens. While it can evaluate residual tumor tissue at the surgical site, it cannot detect invisible micrometastatic disease circulating in the bloodstream or residing in distant organs.

This is one reason why circulating tumor DNA (ctDNA)-based MRD analysis has attracted increasing attention. Across multiple cancer types, patients who achieve both pCR and ctDNA clearance have demonstrated the most favorable outcomes. Conversely, cases have been reported in which patients achieved pCR but remained ctDNA-positive, indicating a substantially higher risk of recurrence.

Ultimately, future MRD assessment is likely to evolve toward an integrated approach that combines pCR, ctDNA, molecular risk factors, and clinical risk factors. Such an approach may be particularly important in cancers like prostate cancer, where recurrence can take many years to become clinically apparent.

Is pCR a Cause or Merely a Marker?

Perhaps the most fundamental question raised by PROTEUS is whether pCR is actually a cause of improved survival or simply a marker reflecting treatment efficacy.

In PROTEUS, the pCR/MRD rate increased dramatically to 8.9%, compared with just 1.0% in the control arm. However, it remains unclear whether the improvements in MFS and EFS observed across the entire study population can truly be explained by this approximately 8% increase in pCR alone. Intuitively, it is difficult to conclude that a pathological response difference occurring in fewer than 10% of patients fully accounts for the long-term clinical benefits observed in the overall trial population.

An alternative explanation is that apalutamide contributed to improved MFS and EFS through multiple mechanisms, including shrinking the primary tumor, suppressing radiographically occult micrometastatic disease, and providing sustained inhibition of androgen receptor signaling. In other words, the simultaneous observation of increased pCR and improved survival does not necessarily mean that pCR itself mediated the survival benefit.

This distinction highlights the difference between a prognostic marker and a surrogate endpoint. The fact that patients who achieve pCR tend to have better outcomes is a different issue from whether an increase in pCR can explain improved survival at the population level. While PROTEUS demonstrated the potential relevance of pCR in prostate cancer, it has not yet established pCR as a validated surrogate endpoint capable of fully representing MFS or EFS.

The Message Left by ASCO 2026

PROTEUS was not a negative study. On the contrary, it was an important trial demonstrating that pathological responses and long-term clinical outcomes may indeed be linked in prostate cancer. At the same time, however, the study raised new questions about how pCR should be interpreted.

In breast cancer, pCR has become a powerful surrogate endpoint that has accelerated drug development. In prostate cancer, however, the validation process is still ongoing. The key question moving forward will not simply be whether pCR increases, but rather to what extent that increase contributes to reductions in recurrence and improvements in survival.

ASCO 2026 highlighted the beginning of an era in which pCR must be interpreted alongside molecular MRD biomarkers such as ctDNA. Ultimately, the true lesson of PROTEUS may not be about the failure or success of pCR itself, but rather the recognition that surrogate endpoints can differ across cancer types—and that their validity is established not by biological hypotheses alone, but by the accumulation of consistent clinical evidence over time.

Source: The Bio (https://www.thebionews.net)