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Residual Cancer After Neoadjuvant Tx Predicts High-Risk Prostate Cancer Outcomes

Residual disease burden after intensified neoadjuvant therapy (NAT) using androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPI) for high-risk prostate cancer predicts metastatic recurrence after radical prostatectomy (RP), a new study finds.

Investigators studied 218 patients who participated in 5 neoadjuvant trials at the Dana-Farber Harvard Cancer Center between 2006 and 2018. Nearly all patients (98%) received 6 months of intensified ADT prior to RP. Of patients, 74% received apalutamide or enzalutamide with or without abiraterone. At baseline, PSA levels were below 10 ng/mL in 60%, cT3-4 affected 20%, and Gleason score 9 or 10 was detected in 42%. Median age was 61 years.

At RP, 11% had pathologic complete response and another 11% had residual disease. The median cancer burden was 0.05 cm3 measured in the largest focus in the primary tumor.

At a median 5 years after RP, the overall metastasis-free survival (MFS), the study's primary outcome, was 83%, and the overall survival rate was 98%. The 5-year MFS rate was 98% among patients with pathologic complete response or minimal residual disease compared with 80% in patients without response, Praful Ravi, MB, BChir, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues reported in European Urology.

In a multivariable analysis, the risk for metastasis was significantly higher in patients with cT3-4 stage compared with cT1-2 (hazard ratio [HR], 2.58; 95% CI, 1.38-4.82; P =.003) and Gleason score 9-10 vs 7-8 (HR, 2.29; 95% CI, 1.20-4.36; P =.012). Each increment in residual cancer burden was significantly associated with a 21% increased risk for metastasis (HR, 1.21; 95% CI, 1.01-1.47; P =.039).

MFS at 5 years was 100% for patients with no residual disease compared with 90%, 82%, and 63% for those with residual cancer burden less than 0.003 cm3, 0.003 to 0.672 cm3, and 0.672 cm3 or greater, respectively.

"The depth of pathologic response, measured as [residual cancer burden], was prognostic for MFS," Dr Ravi's team wrote. Patients with residual cancer might be candidates for adjuvant therapy. "Assessment of [residual cancer burden] could serve as a valuable tool in guiding drug development for the neoadjuvant and post-neoadjuvant settings in [high risk localized prostate cancer]."

In an accompanying editorial, Steven Joniau, MD, PhD, and colleagues from the University Hospitals Leuven in Leuven, Belgium, commented: "The study showed for the first time that a pathological response at final pathology is a strong prognostic factor for MFS."

They raised questions about how best to measure residual cancer burden, however. Prostate cancer is multifocal in approximately 60% of cases, they noted, and the primary tumor is often unclear. Whether to include metastatic lymph nodes into the residual disease calculation also has not been resolved. According to the editorialists, results from the ongoing PROTEUS trial (NCT03767244) may further clarify the prognostic value of pathologic response in high risk prostate cancer.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors' disclosures. 

Understanding The FDA Imfinzi Combo Approval For Bladder Cancer Care

Dr. Matthew Galsky highlights the impact of Imfinzi's adjuvant approval for patients with muscle-invasive bladder cancer following cystectomy and chemo.

Adjuvant treatment with Imfinzi (durvalumab) plus chemotherapy, followed by single-agent, adjuvant Imfinzi following radical cystectomy received U.S. Food and Drug Administration (FDA) approval for muscle invasive bladder cancer in March of 2025, marking a milestone in treatment, according to Dr. Matthew Galsky.

In an interview with CURE, Galsky — who serves as a professor of Medicine (Hematology and Medical Oncology) at The Tisch Cancer Institute, part of the Mount Sinai Health System, in New York — discussed what makes this approval significant for patients and providers managing muscle-invasive bladder cancer. He goes on to share that data from the randomized, open-label, multicenter, phase 3 NIAGARA trial evaluated the now-FDA-approved approach, which demonstrated a statistically significant improvement in event-free survival and overall survival.

Galsky is also the director of Genitourinary Medical Oncology, co-director of the Center of Excellence for Bladder Cancer, and associate director for Translational Research, at The Tisch Cancer Institute. Read more on his key takeaways for patients regarding the FDA approval here.

Transcript:

A standard treatment for muscle-invasive bladder cancer is the surgical removal of the bladder. We know that after the bladder is removed, a subset of individuals will experience the cancer reappearing elsewhere in the body, developing metastatic recurrence, typically months to years later.

For decades, doctors attempted to combine chemotherapy with surgery to eradicate any microscopic cancer cells that might be present, aiming to reduce the risk of metastatic recurrence. When chemotherapy is administered before surgery, it's called neoadjuvant therapy. This concept of giving chemotherapy prior to surgery to treat potential microscopic spread of cancer is used in various solid tumors. When chemotherapy is given after surgery, it's known as adjuvant therapy.

For decades, the only neoadjuvant therapy proved beneficial in muscle-invasive bladder cancer was a combination of chemotherapy drugs, including cisplatin. This truly represented the standard treatment approach for many years because nothing had been shown to be superior.

Finally, after several decades, the NIAGARA trial demonstrated that integrating immunotherapy in the pre-surgical and post-surgical periods decreases the risk of metastatic disease development and improves longevity for patients.

Transcript has been edited for clarity and conciseness.

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Imfinzi Combination Shows Efficacy In Bladder Cancer Treatment

Dr. Matthew Galsky discusses the FDA approval of Imfinzi and chemo before and after surgery for muscle-invasive bladder cancer, based on the NIAGARA trial.

Imfinzi plus chemo before and after surgery reduced recurrence and improved survival in muscle-invasive bladder cancer.

In March 2025, the FDA approved neoadjuvant treatment with Imfinzi (durvalumab) plus gemcitabine and cisplatin, followed by single-agent, adjuvant Imfinzi following radical cystectomy in muscle invasive bladder cancer, according to a news release from the United States Food and Drug Administration (FDA).

Notably, the efficacy of the now-FDA-approved approach was evaluated in the randomized, open-label, multicenter, phase 3 NIAGARA trial. In the study, the investigative combination demonstrated a statistically significant improvement in event-free survival and overall survival for patients with muscle invasive bladder cancer who were candidates for radical cystectomy (surgery to remove the urinary bladder).

In an interview with CURE, Dr. Matthew Galsky sat down to discuss the significance of this FDA approval and key takeaways for patients within this population.

"The most important takeaway [message] is that there has been a slow but steady improvement in our ability to treat muscle-invasive bladder cancer," Galsky explained in the interview. "I think we are at a tipping point in the next few years, where the convergence of better therapies and better technologies — specifically, our ability to measure small amounts of cancer with increased precision using better testing — will all come together and potentially completely change the way we treat bladder cancer moving forward."

Galsky is professor of Medicine (Hematology and Medical Oncology), director of Genitourinary Medical Oncology, co-director of the Center of Excellence for Bladder Cancer, and associate director for Translational Research, all located at The Tisch Cancer Institute, the Mount Sinai Health System, in New York, New York.

CURE: To begin, what makes this approval significant for patients and providers managing muscle-invasive bladder cancer?

Galsky: A standard treatment for muscle-invasive bladder cancer is the surgical removal of the bladder. We know that after the bladder is removed, a subset of individuals will experience the cancer reappearing elsewhere in the body, developing metastatic recurrence, typically months to years later.

For decades, doctors attempted to combine chemotherapy with surgery to eradicate any microscopic cancer cells that might be present, aiming to reduce the risk of metastatic recurrence. When chemotherapy is administered before surgery, it's called neoadjuvant therapy. This concept of giving chemotherapy prior to surgery to treat potential microscopic spread of cancer is used in various solid tumors. When chemotherapy is given after surgery, it's known as adjuvant therapy.

For decades, the only neoadjuvant therapy proved beneficial in muscle-invasive bladder cancer was a combination of chemotherapy drugs, including cisplatin. This truly represented the standard treatment approach for many years because nothing had been shown to be superior.

Finally, after several decades, the NIAGARA trial demonstrated that integrating immunotherapy in the pre-surgical and post-surgical periods decreases the risk of metastatic disease development and improves longevity for patients.

The NIAGARA trial demonstrated a 32% reduction in the risk of recurrence and a 25% reduction in the risk of death. How do these results compare with historical outcomes using neoadjuvant chemotherapy alone?

The historical outcomes for patients with muscle-invasive bladder cancer treated with chemotherapy followed by surgery are really mirrored by the control arm of this study, as that was the control arm. Now, patients in this study fared slightly better than what we typically observe historically, likely because our treatment and supportive care have evolved.

However, we know that beyond that standard of care, the addition of immune checkpoint blockade, or [Imfinzi (durvalumab)] — both in the pre-surgical and post-surgical periods — improves our ability to prevent cancer recurrence and allows patients to live longer, even exceeding what we consider the contemporary and historical standard treatment.

What can patients expect during treatment with this combination of immunotherapy and chemotherapy — both in terms of the timeline and potential side effects?

Immune checkpoint blockade involves drugs that we call PD-1 or PDL-1 inhibitors, and Imfinzi is a PDL-1 inhibitor. These drugs have been used alone in various indications and also combined with chemotherapy for a variety of different indications across various solid tumors. So, oncologists are quite accustomed to administering these combinations at this point.

Our extensive experience thus far indicates that when you give immunotherapy with chemotherapy, it does not seem to worsen the side effects of the chemotherapy, nor does the chemotherapy seem to worsen the side effects of the immunotherapy. That said, when you administer two classes of drugs simultaneously, there's a higher overall risk for side effects because you have the potential side effects of each component, but they don't amplify each other.

Regarding side effects, those that can occur with cisplatin-based chemotherapy, in particular, are the ones many people associate with chemotherapy. These can include fatigue, nausea, vomiting, hair loss, an impact on kidney function and neuropathy, such as numbness and tingling in the fingers and toes. Fortunately, many of these side effects are transient and reversible with chemotherapy. Immune checkpoint blockade, or immunotherapy, has a very different side effect profile; many patients experience few to no side effects with it. However, a subset of patients will develop side effects that we refer to as immune-related [side effects].

These involve inflammation of different parts of the body and really mimic what we think of as autoimmune diseases, except usually, when these side effects occur, they affect one organ in an individual rather than multiple organs. For example, one individual might develop inflammation of the skin, called dermatitis, which manifests as a rash or itching. Another person might get inflammation of the bowel, called colitis, which manifests as diarrhea. When these side effects occur, if they're mild, immunotherapy is held. If they're more severe, they are typically treated with steroid medication.

When we give chemotherapy with immunotherapy prior to surgery, in the neoadjuvant setting, it's administered in three-week cycles. During each three-week cycle, treatment is given twice, once in the first week and once in the second week. These three-week cycles are repeated four times, and then surgery is performed. After surgery, the immunotherapy is generally given once a month to complete eight more months of treatment.

What follow-up research or real-world data are needed to further validate the role of this regimen?

There are several other trials testing a similar concept: should we integrate immune checkpoint blockade with cisplatin-based chemotherapy in the perioperative setting, meaning both before and after surgery?

The results of these trials collectively will, of course, enhance our understanding of the full context regarding what is being achieved with these regimens. However, as a standalone trial, NIAGARA led to FDA approval of this regimen and is now an accepted standard of care for use in patients with muscle-invasive bladder cancer.

Transcript has been edited for clarity and conciseness.

For more news on cancer updates, research and education, don't forget to subscribe to CURE®'s newsletters here.

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