Antibody-Drug Conjugates in Prostate Cancer

Introduction

Prostate cancer is one of the most common cancers in men worldwide and remains a leading cause of cancer-related deaths. While many men are diagnosed at an early stage and can benefit from surgery, radiation, or hormone therapies, some cases eventually progress to a more aggressive form called metastatic castration-resistant prostate cancer (mCRPC). This type of prostate cancer no longer responds to standard hormone treatments and can be very difficult to manage.

Over the past two decades, researchers have developed several new options for patients with advanced prostate cancer, including targeted radiation therapies, gene-directed treatments, and immunotherapy drugs. Unfortunately, these treatments only work for a small group of patients, and their overall benefits are often limited. This means there is still a strong need for more effective and precise therapies.

This is where antibody-drug conjugates (ADCs) come in. ADCs are a new type of cancer treatment that combine the precision of antibodies—which can recognize specific markers on cancer cells—with the power of chemotherapy drugs. By attaching the chemotherapy drug directly to the antibody, ADCs are designed to deliver treatment straight to the cancer cell while minimizing damage to healthy cells.

ADCs have already shown impressive results in other cancers, such as HER2-positive breast cancer, where medicines like trastuzumab emtansine and trastuzumab deruxtecan have improved outcomes for many patients. They have also been approved for use in bladder cancer with drugs like enfortumab vedotin.

Now, researchers are exploring whether ADCs could bring the same benefits to men with advanced prostate cancer. Scientists are testing different targets—unique proteins found on prostate cancer cells—that might help ADCs find and attack the cancer more effectively. This growing area of research holds promise for giving men with hard-to-treat prostate cancer new hope for the future.

ADC Targets in Prostate Cancer

Researchers have identified several key proteins on prostate cancer cells that could serve as “addresses” for ADCs. By attaching powerful cancer-killing drugs to antibodies that recognize these proteins, scientists hope to improve treatment for men with advanced prostate cancer. So far, five major targets have been studied: PSMA, TROP-2, STEAP1, TF, and DLL-3. In addition, newer targets such as HER2 and B7-H3 are being explored.

Prostate-Specific Membrane Antigen (PSMA)

PSMA is one of the best-known markers for prostate cancer and has already been widely used in imaging and radiotherapy. Clinical trials are now testing ADCs that deliver chemotherapy directly to PSMA-positive cancer cells. Some studies have shown encouraging signs, such as reductions in prostate cancer markers in the blood, especially in patients who had not received chemotherapy before. However, side effects like nerve damage, infections, and low blood counts have been challenges, and researchers are working on finding the right balance between effectiveness and safety.

TROP-2

TROP-2 is a protein found on the surface of many cancers, including prostate cancer. ADCs targeting TROP-2—such as sacituzumab govitecan—have already been approved for breast and bladder cancer. Early studies in prostate cancer show that some patients may benefit, though side effects like low white blood cell counts and diarrhea can occur. Several ongoing trials are now testing next-generation TROP-2 ADCs, alone or in combination with other drugs, to see if they can bring more consistent results.

STEAP1

STEAP1 is a newer protein target that is mainly found in prostate cancer cells but rarely in healthy tissues, making it an attractive candidate for precision therapy. Early studies using STEAP1-targeted ADCs have shown that the drugs can reach prostate tumors, as seen on PET scans, but the actual anti-cancer effects so far have been modest. Research is ongoing to improve how these drugs work while minimizing side effects.

Tissue Factor (TF)

TF is a protein linked to both blood clotting and cancer growth. One ADC targeting TF, called tisotumab vedotin, has already been approved for use in cervical cancer. Trials are now testing it in prostate cancer as well. While the drug has shown some activity in other cancers, results in prostate cancer have been limited so far, and side effects such as nausea, abdominal pain, and low blood counts have been reported.

DLL-3

DLL-3 is a marker mainly found in rare prostate cancers that develop “neuroendocrine” features, a more aggressive form of the disease. An ADC called rovalpituzumab tesirine (Rova-T) was tested in patients with DLL-3–positive tumors. While some patients did respond, the benefits were limited, and serious side effects—including fluid buildup and infections—led to the discontinuation of its development in prostate cancer.

Emerging Targets: HER2 and B7-H3

In addition to these five main targets, researchers are also looking at HER2 (well-known in breast cancer) and B7-H3, a newer immune-related protein that may play a role in prostate cancer progression. Several early-phase trials are now underway to test ADCs against these proteins. These studies will help determine whether they could open new doors for treatment in the future.

Discussion and Conclusion

Currently, research on antibody-drug conjugates (ADCs) for prostate cancer remains in its early stages. Some clinical trials indicate that tumor markers show significant reduction in certain patients after using these drugs, particularly in those who have not undergone chemotherapy, demonstrating better efficacy and survival outcomes. This raises an important question: Would using ADCs at an earlier disease stage yield superior results?

However, overall, ADC efficacy has not yet surpassed existing standard treatments, such as newer hormone therapies or conventional chemotherapy. Additionally, some patients must discontinue treatment due to side effects—particularly neurological issues like numbness and sensory abnormalities in the hands and feet—which also impacts efficacy. Furthermore, different studies employ inconsistent criteria for evaluating efficacy—some rely on PSA levels, others on imaging assessments—making direct comparisons difficult. Overall, we have yet to establish the optimal method for comprehensively measuring ADC's role in prostate cancer.

Prostate cancer, particularly in its castration-resistant and metastatic stages, remains a significant medical challenge. The emergence of ADCs offers new hope, but current evidence is insufficient to declare them a “silver bullet.” Future studies—more numerous and longer-term—are needed to confirm whether ADCs can genuinely improve patient survival and quality of life.

Source

https://pmc.ncbi.nlm.nih.gov/articles/PMC9983052/

Assessed and Endorsed by the MedReport Medical Review Board