New Therapy Could Reverse Treatment Resistance in Prostate Cancer

Key Points

• Overall, prostate cancer survival rates are high, especially with early diagnosis, but the disease becomes much more challenging to treat once it spreads to other parts of the body.
• Metastatic castration-resistant prostate cancer doesn't respond to the usual anti-androgen therapies used to combat the disease.
• Researchers have developed a new treatment option that may help stop castration-resistant prostate cancer from progressing.

Prostate cancer is generally manageable, particularly when it is diagnosed early.

The prognosis for patients with metastatic castration-resistant prostate cancer is not so favorable, however. A majority of those diagnosed at this stage die within three years. This type of advanced disease can hijack a patient's immune system and wield it to resist standard treatments for prostate cancer and continue to spread.

Blocking the signals tumors use to recruit white blood cells could reverse the disease's treatment resistance and stop tumor growth, according to early clinical trials.

What is the current treatment for metastatic castration-resistant prostate cancer?

In 2023, roughly 288,300 people in the United States were diagnosed with prostate cancer, and about 34,700 died from the disease, according to the American Cancer Society (ACS). About 1 in 8 American men will be diagnosed with prostate cancer.

The five-year relative survival rate for local or regional forms of prostate cancer is more than 99 percent, per the ACS. When the cancer metastasizes or spreads to distant parts of the body, that rate drops to 32 percent, mainly because effective treatment options are limited.

"In the initial stages, almost all prostate tumors are 'castration sensitive,' meaning androgen deprivation therapy (ADT) alone can stop their growth," said Risa L. Wong, M.D., a genitourinary oncologist at UPMC Hillman Cancer Center in Pittsburgh. 

ADT, or testosterone suppression, uses medications or surgery to intercept the body's androgen receptor pathway, which produces the hormones prostate tumors need to grow and survive.

"As prostate cancer progresses, though, it can develop resistance to anti-androgen treatment options, enabling the tumor to keep growing despite a very low testosterone—or 'castrate'—state," Wong said. "At that point, it's classified as castration-resistant."

People with castration-resistant prostate cancer may continue receiving hormone therapy along with chemotherapy or radiation, according to the Canadian Cancer Society. Doctors may also administer targeted therapy, which uses medications to target specific molecules on or inside cancer cells to stop their growth.

What is the role of myeloid white blood cells in prostate cancer?

Myeloid blood cells, a type of white blood cell primarily found in bone marrow, usually deploy to areas of inflammation to help the body fight infections. Research suggests prostate tumors may also co-opt them to grow, progress and resist treatment.

"People with prostate cancer tend to have higher levels of a particular subtype of myeloid white blood cells, called myeloid-derived suppressor cells—known as MDSCs—both inside the tumors and circulating in their blood," Wong said.

Research suggests cancer cells tend to release substances that attract MDSCs by binding to a receptor called CXCR2 on MDSCs' surface.

"When MDSCs are attracted to cancer tumors in high numbers, they appear to help the tumors survive by helping the cancer cells evade the body's immune system and possibly help the cancer survive in other ways, as well," Wong said. "This is an area of active research, and scientists are still working to understand the relationship between MDSCs and cancer fully."

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How can combination therapy potentially help prostate cancer patients?

In a recent phase 1 study, researchers at the Institute of Cancer Research in London used a combination of the experimental drug AZD5069 and enzalutamide, an anti-androgen medication commonly used in prostate cancer treatment, to treat patients with metastatic castration-resistant prostate cancer.

After treatment, the researchers measured the patients' tumor sizes, levels of prostate-specific antigen (PSA)—a protein excreted by the prostate gland and prostate tumors—and levels of cancer cells circulating in the blood.

In 5 of 21 patients (24 percent), the tumors were more than 30 percent smaller, PSA levels dropped significantly or the number of cancer cells in the body decreased. Researchers also found patients who received treatment had lower levels of myeloid cells in their blood and within their tumors.

The findings were published in the journal Nature in October 2023.

"AZD5069 is a CXCR2 inhibitor, meaning it works by blocking other substances from binding to CXCR2," Wong said.

The idea is that with AZD5069 in a person's system, cancer cells can't easily attract MDSCs because the drug prevents them from doing so.

The study's preliminary data suggests a therapeutic benefit from combining enzalutamide—a standard androgen receptor pathway inhibitor—with a CXCR2 inhibitor that targets myeloid cells, according to Ravi A. Madan, M.D., the head of prostate cancer clinical research at the Center for Cancer Research, National Cancer Institute, in Bethesda, Maryland.

"These data results suggest that this treatment combination with a CXCR2 inhibitor can reverse resistance to very effective and well-tolerated androgen receptor pathway inhibitors such as enzalutamide," Madan said.

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"These early findings are exciting and show the potential of a new treatment option that may help to combat advanced prostate cancer and other malignancies involving MDSCs," Wong said. "As always, further studies with greater numbers of patients are necessary to clarify the safety and efficacy of the drug, but I look forward to seeing the results of that future work."

Madan noted that the study was a valuable contribution to ongoing research that emphasizes components of prostate cancer's tumor microenvironment that haven't been extensively explored. For the past decade, much of the focus has been on T-cells because of the clinical success of immune checkpoint inhibitors and a general enthusiasm for chimeric antigen receptor (CAR) T-cell therapies.

The study highlights that the prostate cancer tumor immune microenvironment consists of other targets beyond immune checkpoint inhibitors. And that's good, because they work in prostate cancer for only a small subset of patients, less than 5 percent, he added.

"This study also provides an intriguing potential connection between myeloid cells and androgen receptor pathway signaling, which may prove to provide a mechanism to extend the efficacy of front-line androgen receptor pathway inhibitors in patients with prostate cancer," Madan said.

The bottom line

Many advances in prostate cancer treatment have been made in recent years. Overall, men with the condition now live longer and have less disease burden than ever before.

Prostate cancer can still be deadly.

Although more research is needed, AZD5069 and drugs like it could provide hope for men with advanced forms of prostate cancer, for whom treatment options are currently limited.

Many doctors recommend that men ages 55 to 69 should get a prostate exam every three to five years. If you're outside those age ranges and have any concerns, don't hesitate to talk to your healthcare provider.