How a Neoadjuvant Microdevice Could Transform Treatment of Prostate Cancer

Clinicians have traditionally chosen from a menu of drug therapies including hormones, PARP inhibitors, and immunotherapies to treat prostate cancer. What has been lacking, however, is a reliable way to know in advance which drug or combination of drugs will work best for a given patient.

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Three Mass General Brigham investigators—Adam S. Kibel, MD, Oliver Jonas, PhD, and Nobuhiko Hata, PhD—are aiming to fill that gap. They are in the early stages of developing an implantable microdevice (IMD) that delivers micro-doses of drugs directly into prostate tumors prior to planned radical prostatectomy.

"The idea is that we could put these devices into a patient, pull them out after a couple days, and see whether the tumor responds to the drug or drugs," says Dr. Kibel, chief of Urology at Mass General Brigham. "This is essentially proof-of-concept work. Eventually, we'd like to be able to say definitively whether the patient's tumor will respond before using a drug. But we're not there yet."

A Look at the Clinical Workflow and Key Takeaways

Previously, Dr. Kibel and his colleagues had noted the divergent responses to treatments among patients with prostate cancer. Whereas some patients had an outstanding response, others had a minimal response.

“Was this because some tumors were resistant to all systemic therapy, or were they resistant to that specific therapy?” Dr. Kibel says. “Basically, the question raised was, could we identify both good and poor responders for each drug earlier and perhaps tailor the treatment choice based these results?”

The IMD, about 3 millimeters long, is intended for patients with MRI-visible prostate tumors. Each device, or chip, contains one or more drugs. With the patient in the lithotomy position, up to four chips are placed transperineally under MRI guidance. Drug diffusion is limited to micrometers around each chip; no drug enters the system.

The prostatectomy occurs 48 hours after implantation. Following localization by radiology, each chip is excised by pathology for scientific analysis.

"The approach is like antibiotic susceptibility testing but for cancer cells," Dr. Kibel says. "Rather than testing multiple antibiotics on bacteria to see which ones are effective, we're testing chemotherapies and other cancer drugs on tumors."

Dr. Kibel and his colleagues have studied the delivery of assorted immunotherapies, PARP inhibitors, androgen receptor inhibitors, targeted therapies, and chemotherapy agents—including combinations of up to three drugs.

Preliminary takeaways of clinical interest include:

• Apoptotic response across all drugs/drug combinations ranged from near 0% to 80%, underscoring significant inter- and intra-tumor heterogeneity.
• Most of the drugs/drug combinations demonstrated response but often in only a small number of patients, with wide confidence intervals indicating significant inter-patient variability.
• Not surprisingly, combinations featuring the immunotherapies ipilimumab or ipatasertib were least successful in inducing apoptosis. But that doesn’t mean these treatments won’t work. For instance, docetaxel plus the PARP inhibitor olaparib registered around 18%, the highest score, and docetaxel alone was about 12%. In contrast, docetaxel plus ipilimumab was roughly 4%. “This is totally consistent with the mechanism of action for immunotherapy, which does alter tumor behavior through apoptosis,” Dr. Kibel says.
• Talazoparib, a PARP inhibitor, "may have an effect in patients that don't have the underlying molecular signature for PARP inhibition," according to Dr. Kibel. He adds that this finding needs to be studied in more patients.
• Abemaciclib, a CDK 4/6 inhibitor not yet studied in prostate cancer, also showed a response. "This finding highlights the IMD's value in exploring novel drug combinations," Dr. Kibel says.

Pursuing a More Personalized Treatment Approach

In terms of other use cases, the IMD also holds promise as a biomarker tool. According to Dr. Kibel, it could serve this purpose in two distinct ways. "The chip itself could be a biomarker—you could use the response you see in the chip to dictate which drugs the patient gets," he explains. "Or you could use the chip to help in biomarker discovery to identify things in the tumor that would also be in other tumors to help predict response to a particular drug."

Ultimately, the Mass General Brigham team hopes to move prostate cancer treatment away from trial-and-error drug selection in favor of a more personalized approach. Dr. Kibel envisions a workflow in which the IMD is implanted, removed, and analyzed to identify the optimal drug regimen for individual patients, including those with metastatic disease.

“The ultimate goal is to ensure that every patient receives the treatment most likely to cure their cancer while minimizing side effects,” he says. “The IMD itself—or the biomarkers we discover through its use—could help make that kind of personalized, targeted therapy possible.”

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