Breakthroughs in Prostate Cancer: Insights from the MetaCURE Multi-Modal Trial

Understanding the Frontier of Prostate Cancer Treatment

For decades, the standard of care for prostate cancer has followed a relatively linear progression. When the disease is discovered early and localized to the prostate, surgery or radiation is often curative. However, for patients diagnosed with high-risk localized disease or those where the cancer has begun to spread—known as metastatic disease—the path forward becomes significantly more complex. Historically, the primary weapon against advanced prostate cancer has been Androgen Deprivation Therapy (ADT), which starves the cancer cells of the testosterone they need to grow. While effective, ADT alone is rarely a permanent cure for advanced cases.

The Shift Toward Multi-Modal Therapy (MMT)

As our understanding of cancer biology has evolved, so too has our strategy for attacking it. Rather than relying on a single mode of treatment, researchers are increasingly looking toward Multi-Modal Therapy (MMT). This approach combines several different types of treatment—such as intensive hormone therapy, surgery, and radiation—simultaneously or in rapid succession. The goal is to hit the cancer hard and from multiple angles before it has the chance to develop resistance.The MetaCURE trial, a Phase 2 randomized clinical study, represents a significant step forward in this effort. By testing a combination of modern hormonal agents (Apalutamide and Abiraterone) alongside traditional surgery and targeted radiation, the trial sought to see if a intensive, 10-month ‘burst’ of therapy could lead to long-term remission, even after the drugs were stopped.

The MetaCURE Trial Design: Cohorts A and B

The study focused on two specific groups of patients who are at high risk for progression. Cohort A consisted of patients with high-risk localized disease, meaning the cancer was aggressive but had not yet spread beyond the prostate area. Cohort B included patients with low-volume metastatic disease, often referred to as oligometastatic cancer, where only a few spots of cancer were detected outside the primary site.The treatment protocol was intensive. Both groups received a ‘backbone’ of androgen deprivation therapy combined with Apalutamide (a next-generation androgen receptor inhibitor). Half of the patients also received Abiraterone acetate plus prednisone. This intensive drug regimen lasted for 10 months. However, the systemic therapy was only one part of the equation. Patients in Cohort B also received stereotactic body radiotherapy (SBRT) at the 4-month mark to target metastatic sites. At month 6, all patients underwent a radical prostatectomy—the surgical removal of the prostate. If necessary, postoperative radiotherapy was administered at 10 months.

A Patient’s Journey: The Case of Robert

To understand the impact of this intensive regimen, consider the fictional case of Robert, a 64-year-old retired architect from Chicago. Robert was diagnosed with low-volume metastatic prostate cancer after a routine screening showed a rapidly rising PSA level and a follow-up scan revealed two small lesions on his pelvic bone.In the traditional treatment model, Robert might have been placed on lifelong hormone therapy. While his PSA would likely drop, he would face the long-term side effects of low testosterone, such as fatigue, bone loss, and metabolic changes, with the knowledge that the cancer would likely eventually return.By participating in a trial like MetaCURE, Robert’s treatment was compressed and intensified. For 10 months, he took a combination of powerful hormone-blocking medications. At four months, doctors used precision radiation to ‘zap’ the two spots on his bone. At six months, his primary tumor was surgically removed. By the end of month 10, all treatments were stopped. The goal for Robert was ‘Testosterone Recovery’—allowing his body to return to normal hormonal levels while keeping the cancer in a state of undetectable remission.

What the Data Tell Us: A Rapid Readout of Efficacy

The results of the MetaCURE trial provide a fascinating look at how aggressive early intervention affects the body. Researchers used two primary ways to measure success: the ‘pathologic’ response at the time of surgery and the long-term PSA levels after testosterone returned to normal.The following table summarizes the key outcomes:

Measure of Efficacy	Cohort A (High-Risk Localized)	Cohort B (Low-Volume Metastatic)
Pathologic Complete Response (pCR) or Minimal Residual Disease (MRD)	12%	15%
Undetectable PSA at 24 Months (with T recovery)	61%	39%

A pCR or MRD means that when the surgeon removed the prostate, there was either no cancer left or only a tiny trace (less than 5mm). While these numbers (12-15%) might seem low at first glance, they represent a significant achievement in a high-risk population. More importantly, the secondary endpoint showed that 61% of localized patients and 39% of metastatic patients maintained an undetectable PSA even after their testosterone levels recovered at the two-year mark. This suggest that for a significant subset of patients, the intensive ‘multi-modal’ burst was enough to keep the cancer at bay without the need for lifelong medication.

Redefining Success: Intermediate Endpoints

One of the most important aspects of the MetaCURE trial is not just the treatment itself, but how we measure its success. Traditionally, prostate cancer drug trials take a decade or more because they measure ‘Overall Survival.’ Since prostate cancer can grow slowly, it takes a long time to see if a drug truly extends life.The MetaCURE team argued for the use of ‘intermediate endpoints’ like pCR and MRD. By looking at the tissue at the time of surgery, researchers can get a ‘rapid readout’ of whether a drug is working. If a drug combination can eliminate the tumor in six months, it is a strong candidate for larger, faster studies. This framework accelerates drug development, potentially bringing life-saving treatments to market years earlier than the traditional model would allow.

Safety and Feasibility: Is the Intensive Approach Practical?

A common concern with intensive therapy is the ‘toxicity’ or the burden of side effects on the patient. The MetaCURE trial demonstrated that this multi-modal approach is feasible and safe. While the 10-month period was intense for patients like Robert, the majority were able to complete the protocol. The trade-off—a year of intensive treatment versus a lifetime of continuous hormone suppression—is a choice many patients and clinicians are increasingly willing to consider.Expert insights from the study authors, including Dr. Howard Scher and his colleagues at Memorial Sloan Kettering Cancer Center, emphasize that this approach allows for a ‘window of opportunity.’ By intervening when the cancer is still ‘hormone-naïve’ (meaning it hasn’t been treated with hormones yet and hasn’t developed resistance), the treatments are significantly more effective.

Expert Insights and Future Directions

The success of MetaCURE has already informed the design of next-generation clinical trials. Researchers are now moving toward ‘adaptive’ trials. In an adaptive trial, the treatment can be adjusted in real-time based on how the patient is responding. If a patient shows a rapid drop in PSA or a positive response on an early scan, they might continue the intensive therapy. If not, they can be quickly pivoted to a different drug.This moves us closer to the goal of ‘Precision Medicine’ in oncology—the right treatment for the right patient at the right time. For patients with oligometastatic disease, who were once thought to be incurable, the MetaCURE results offer a glimpse of a future where long-term, treatment-free remission is a realistic goal.

Conclusion: A New Chapter in Prostate Cancer Care

The MetaCURE trial represents a paradigm shift in how we approach aggressive prostate cancer. By proving that a multi-modal strategy is safe and can provide a rapid assessment of drug efficacy, it sets the stage for a new era of clinical research. For patients, it offers the hope of ‘hitting hard and hitting early,’ potentially changing the trajectory of their disease from a chronic condition to one that can be managed with a finite, intensive course of therapy.As we look forward, the integration of surgery, radiation, and novel systemic therapies will likely become the cornerstone of treatment for those at the highest risk. The path to a cure is rarely a straight line, but frameworks like MetaCURE are helping us find the shortcuts.

References

McHugh D, Dallos M, Teo MY, McBride SM, Gopalan A, Arfe A, Gaffney CD, Amjed M, McCann PJ, Benoliel H, Autio KA, Goh AC, Derudder K, Ryan CJ, Szmulewitz RZ, Morgans AK, Bubley GJ, Gupta S, Klein EA, Nguyen PL, Kibel AS, Wagner AA, Kaplan ID, Eggener S, Einstein DJ, Acosta AM, Tendulkar R, VanderWeele DJ, Catalona W, Sachdev S, Liauw SL, Eastham JA, Taplin ME, Scher HI. Accelerating Drug Development in Hormone-Naïve Prostate Cancer Through Multi-Modal Therapy Strategies: The MetaCURE Phase 2 Randomized Clinical Trial. Clin Cancer Res. 2025 Nov 20. doi: 10.1158/1078-0432.CCR-25-2679. Epub ahead of print. PMID: 41263694.