Prostate cancer is one of the most common cancers among men worldwide, and its incidence is rising annually with the aging global population. While traditional treatments such as surgery, radiation therapy, and chemotherapy are effective in the early stages, their effectiveness significantly decreases for patients with advanced and drug-resistant prostate cancer. In recent years, antibody-drug conjugates (ADCs) have emerged as a novel targeted therapy, becoming an important research direction in cancer treatment. ADCs combine the targeting characteristics of monoclonal antibodies with the toxic effects of chemotherapy drugs, allowing for more precise and effective treatment, especially showing promising clinical prospects in prostate cancer therapy.

What is Prostate Cancer?

Prostate cancer refers to cancer that occurs in the prostate gland tissue. The prostate is part of the male reproductive system, located below the bladder and in front of the rectum. This gland is responsible for secreting prostate fluid, which is a major component of semen. Prostate cancer usually originates from the glandular epithelial cells of the prostate and is often asymptomatic in its early stages, making it commonly discovered during screening or examinations for other conditions. Prostate cancer exhibits a wide range of malignancy, with most cases growing slowly in the early stages. However, as the disease progresses, some cancer cells may become more aggressive and even metastasize, commonly to the bones and lymph nodes.

Types of Prostate Cancer

Prostate cancer is usually divided into several categories, the most common being adenocarcinoma, which makes up more than 95% of all prostate cancer cases. Adenocarcinoma comes from the glandular cells of the prostate, usually develops slowly, and there are no obvious symptoms early on. Even though the majority of adenocarcinomas are benign, some can develop into very aggressive cancers later in life. Small-cell prostate cancer is a less common form and one that grows quickly, doesn't respond well to traditional therapies (such as chemotherapy and radiation) and has a bad prognosis. Dedifferentiated prostate cancer and papillary prostate cancer are different as well. Dedifferentiated cancer cells are typically devoid of cell architecture and function, so they resist most orthodox treatments and thus are much harder to treat. The biology, symptoms and response to treatment vary between types of prostate cancers, influencing treatment approaches.

Immunotherapy for Prostate Cancer

Immunotherapy for prostate cancer has gradually become an important area of research and treatment in recent years, especially for advanced and drug-resistant prostate cancer patients, offering new hope for treatment. Immunotherapy works by activating the patient's immune system to enhance its ability to recognize and attack tumor cells, overcoming the limitations of traditional therapies. The main types of immunotherapy for prostate cancer include immune checkpoint inhibitors, cancer vaccines, cell-based immunotherapies, and ADCs.

• Immune Checkpoint Inhibitors

Immune checkpoint inhibitors enhance the anti-tumor response of T cells by removing the immune system's mechanisms of immune evasion in tumors. CTLA-4, PD-1, and PD-L1 are the most studied immune checkpoints, with drugs such as ipilimumab (CTLA-4 inhibitor) and pembrolizumab (PD-1 inhibitor) demonstrating significant efficacy in various cancers. However, in prostate cancer, monotherapy with immune checkpoint inhibitors has shown limited effectiveness, particularly in advanced patients. Some studies suggest that prostate cancer has a weaker response to immune checkpoint inhibitors, which may be related to the tumor microenvironment and immune tolerance. As a result, research on immune therapy for prostate cancer is gradually shifting toward combination therapy strategies, such as combining immune checkpoint inhibitors with other immunotherapies or traditional treatments, in hopes of achieving better therapeutic outcomes.

• Cancer Vaccines

Cancer vaccines aim to activate the patient's immune system to recognize and attack tumor cells. For prostate cancer, Sipuleucel-T is the only approved cancer vaccine. It stimulates the immune system to enhance the immune response against prostate-specific antigens, showing survival benefits in some patients. However, the efficacy of Sipuleucel-T varies widely among patients, and its high treatment cost limits its application. Enhancing its efficacy remains a key direction for future research.

• Cell-Based Immunotherapies

Cell-based immunotherapies enhance the function of T-cells or natural killer cells to boost the body's antitumor immune response. In prostate cancer treatment, CAR-T cell therapy is becoming a research hotspot. CAR-T cell therapy involves genetically modifying a patient's T-cells to recognize and kill prostate cancer cells. Although CAR-T has achieved significant efficacy in some hematologic cancers, its application in prostate cancer faces challenges, mainly due to immune evasion mechanisms of prostate cancer cells and the complexity of the tumor microenvironment. Current research focuses on improving T-cell recognition and enhancing their persistence in the tumor microenvironment to improve efficacy.

• Antibody-Drug Conjugates

ADC is a therapeutic strategy that combines monoclonal antibodies with cytotoxic drugs, allowing precise targeting of cancer cells while minimizing damage to normal tissues. The advantage of ADCs lies in their ability to use monoclonal antibodies to recognize specific antigens on prostate cancer cell surfaces (such as PSMA, prostate-specific membrane antigen) and directly deliver cytotoxic drugs to tumor sites. ADCs can achieve precise treatment by releasing the toxic drug only inside cancer cells through the antibody's specific recognition of tumor cell surface markers. Current research on prostate cancer ADCs primarily focuses on developing PSMA-targeted ADCs, some of which have shown good preclinical results. For example, PSMA-targeted ADCs, combining potent cytotoxic drugs like microtubule inhibitors or DNA damage repair inhibitors, can effectively suppress tumor growth, particularly in advanced prostate cancer patients where traditional therapies are ineffective, showing significant therapeutic efficacy.

Antibody Drug Conjugate Prostate Cancer

ADCs consist of a linker, payload, and monoclonal antibody (mAb). They combine the advantages of high specificity targeting and potent cytotoxic effects, achieving precise and efficient destruction of cancer cells. ADCs have become one of the hot topics in cancer drug development. Since the first ADC drug, Mylotarg®, was approved by the FDA in 2000, by January 2024, a total of 15 ADC drugs have been approved globally for the treatment of hematologic malignancies and solid tumors. Additionally, over 100 ADC candidates are currently in various stages of clinical trials.

Fig. 1. ADC targets in prostate cancer cells (Cureus. 2023, 15(2): e34490).

On March 23, 2022, Novartis announced that the U.S. FDA had approved the company's targeted radioligand therapy, Pluvicto (lutetium Lu 177 vipivotide tetraxetan, 177Lu-PSMA-617), for the treatment of PSMA-positive, treatment-progressed, castration-resistant prostate cancer (mCRPC) patients. Pluvicto's approval was based on Phase III clinical data from the VISION trial, which showed an overall response rate (ORR) of 30%, with a complete response rate (CR) of 6%, and a 38% reduction in the risk of death. Pluvicto is the first FDA-approved therapeutic drug targeting PSMA (PS: Novartis' peptide radionuclide conjugate should be considered a PDC). No ADC has yet been approved for prostate cancer, but several ADCs targeting different antigens, such as PSMA, TROP-2, STEAP1, and SLC44A4, are currently under clinical investigation.

ADC Products for Prostate Cancer

ADC Targets in Prostate Cancer

Androgen deprivation therapy (ADT) is a crucial treatment for prostate cancer (PCa). However, for castration-resistant disease, treatment options also include chemotherapy, anti-androgen therapy, radiolabeled isotope therapy, gene-targeted therapy, immune checkpoint inhibitors, and autologous cell immunotherapy. Key targets for PCa include prostate-specific membrane antigen (PSMA), prostate six-transmembrane epithelial antigen 1 (STEAP-1), solute carrier family 44 member 4 (SLC44A4), trophoblast cell surface antigen (Trop-2), and B7-H3. Below are descriptions of these targets and the ADC drugs in clinical stages targeting them.

• PSMA-Targeted ADCs

PSMA is a type II transmembrane glycoprotein highly specific to the prostate. It has a carboxypeptidase activity that catalyzes the hydrolysis of N-acetylasparaginylglutamate to glutamate and N-acetylasparagine. PSMA consists of an intracellular domain of 19 amino acids, a transmembrane domain of 24 amino acids, and an extracellular domain of 707 amino acids. The FOLH1 (folate hydrolase 1) gene encoding PSMA is located on chromosome 11, and its expression is regulated by androgen signaling. PSMA is most highly expressed on the surface of prostate epithelial cells, with lower expression found in the renal proximal tubules, small intestine brush border, Schwann cells, and astrocytes. Upon activation, PSMA is rapidly internalized within cells. PSMA is highly expressed in most PCa cells (100-1000 times that of normal levels), including those in advanced disease, castration-resistant cases, and poorly differentiated disease. Additionally, PSMA has a high internalization rate in PCa cells. Several PSMA-targeted ADCs currently in development include MLN2704, PSMA-MMAE, MEDI3726, BIND014, and ARX517.

• MLN2704 is an ADC that conjugates a humanized monoclonal antibody MLN591 with maytansinoid DM1. Phase 1/2 dose-escalation trials indicated dose-limiting neurotoxicity with MLN2704, and its activity in metastatic castration-resistant prostate cancer (mCRPC) was limited. The instability of the disulfide linkage and rapid deconjugation led to neurotoxicity and a narrow therapeutic window. Consequently, the development of MLN2704 has been discontinued.
• PSMA-MMAE is a fully human IgG1 anti-PSMA monoclonal antibody conjugated to monomethyl auristatin E (MMAE), which binds to PSMA-positive cells and induces cytotoxicity. In a Phase 1 study, PSMA-MMAE showed good tolerance and reduced serum prostate-specific antigen (PSA) levels and circulating tumor cells (CTCs). A further Phase 2 trial of PSMA-MMAE in mCRPC patients receiving abiraterone/enzalutamide (ABI/ENZ) showed some antitumor activity, with reduced PSA levels and CTCs in some patients.
• MEDI3726 is an ADC targeting PSMA and carrying the pyrroloquinazoline-based payload, tesirine. A Phase I study evaluated the efficacy of MEDI3726 monotherapy in mCRPC patients who had received abiraterone and/or enzalutamide and taxane chemotherapy. Despite limited clinical activity, particularly at higher doses in this generally poor prognosis patient group, emerging treatment-related toxicities limited the duration of treatment and prevented further planned dose escalation.
• In a Phase II clinical trial of mCRPC patients who had not received chemotherapy, BIND-014 (a novel PSMA-ADC) showed good tolerability, and patients may benefit from the treatment. Optimizing dosage administration, combining with more suitable cytotoxic drugs, and selecting appropriate patients are the directions for improving the efficacy of PSMA-ADC in the future.
• ARX517, a proprietary anti-PSMA ADC by AMBRX, has shown encouraging monotherapy safety and efficacy data in advanced PCa patients. In an ongoing Phase 1 dose-escalation trial (APEX-01), early clinical data showed that in three metastatic prostate cancer patients receiving ARX517 treatment, PSA levels dropped by more than 50% from baseline. No serious adverse events (SAEs) or dose-limiting toxicities (DLTs) were observed. These data provide early evidence for the concept of monotherapy ARX517 as a potential treatment for advanced PCa.

• Trop-2-Targeted ADCs

Trop-2 is a transmembrane calcium signaling transducer that is overexpressed in many epithelial cancers and is believed to be associated with disease progression and metastasis, including the development of PCa. Trop-2 contains a 274-amino acid extracellular epidermal growth factor-like repeat region, which includes three structural domains, a cysteine-rich domain, a thyroglobulin type 1 domain, and a cysteine-poor domain. This molecule spans the membrane with a cytoplasmic tail, which has a serine residue at position 303 that can be phosphorylated. The molecule has four N-glycosylation sites in its extracellular domain. Sacituzumab govitecan (Trodelvy) is a Trop-2-directed ADC that uses SN-38 as the active payload. It has been approved by the FDA for the treatment of advanced triple-negative breast cancer and is currently being studied for other indications. IMMU-132 is an ongoing Phase II study designed to evaluate the safety and efficacy of SG in mCRPC patients who have progressed on next-generation anti-androgens (enzalutamide, apalutamide, or abiraterone acetate). The primary endpoint is PSA response rate, defined as a PSA decline of ≥50% within 9 weeks of treatment. Secondary endpoints include radiographic progression-free survival (PFS), overall survival (OS), and toxicity rates. A total of 55 patients will participate in the study.

• STEAP1-Targeted ADCs

The STEAP-1 protein is a 339-amino acid cell surface antigen that may act as an ion channel or protein transporter. In humans, the STEAP-1 gene is located on chromosome 7. An IHC study has confirmed its high expression in prostate epithelial cells, particularly at cell-cell junctions. STEAP-1 expression has been observed in all clinical stages of PCa. In non-prostate tissues, STEAP-1 is moderately expressed in bladder cells and overexpressed in cancers outside of PCa, such as Ewing's sarcoma, bladder cancer, colon cancer, and ovarian cancer. STEAP regulates tumor growth by modulating intracellular communication between tumor cells and the stroma. Its expression profile makes it a promising drug target. Additionally, STEAP is used in peptide-based vaccines. A preclinical study of PCa and BCa xenografts demonstrated that anti-STEAP antibodies could inhibit tumor growth. Vandortuzumab vedotin (VV) is the only ADC currently targeting STEAP-1 in PCa research. A Phase I study assessed the safety and pharmacokinetics of increasing doses of VV (DSTP3086S) in mCRPC patients. A total of 84 patients were enrolled. The dose-escalation group included patients receiving 0.3-2.8 mg/kg VV intravenously every 3 weeks (28 patients) or weekly (7 patients). The initial expansion cohort included 10 patients treated with 2.8 mg/kg, while two additional expansion cohorts included 39 patients treated with 2.4 mg/kg. The most common adverse events (AEs) were fatigue (56%), peripheral neuropathy (51%), and nausea (38%). Among the 77 patients, 31% experienced grade 3 or 4 AEs. In patients receiving >2 mg/kg of the study drug, 18% achieved a PSA decline of ≥50%, 6% showed a radiographic response, and 59% showed conversion of circulating tumor cells (CTCs). The study confirmed that DSTP3086S ADC has acceptable safety and demonstrates activity in mCRPC patients.

• SLC44A4-Targeted ADCs

SLC44A4, or choline transporter-like protein 4, is a transmembrane protein belonging to the choline transporter family. SLC44A4 is involved in the synthesis of non-neuronal acetylcholine and is expressed in epithelial secretory prostate cells. IHC studies have shown that SLC44A4 is upregulated in several tumors, including 85% of primary PCas. Higher expression has been demonstrated in poorly differentiated tumors. In vivo studies have revealed that SLC44A4-directed antibodies have antitumor activity in both androgen-dependent and androgen-independent tumor xenografts. ASG-5ME is a clinical-stage SLC44A4-targeted ADC. A Phase I clinical trial aimed to determine the maximum tolerated dose (MTD) of ASG-5ME in metastatic or non-mCRPC patients. The study was divided into two parts: the first part focused on identifying the safe dose of ASG-5ME, while the second part evaluated its safety and antitumor activity. A total of 46 patients participated in the study. Twenty-six patients were included in the dose-escalation group, which consisted of seven cohorts with doses ranging from 0.3 to 3 mg/kg. Twenty patients were included in the dose-expansion cohort and received 2.4 or 2.7 mg/kg of the investigational drug. Twenty-five percent of the evaluated patients achieved a PSA response with a decline of >50%. According to RECIST 1.1 criteria, stable disease (SD) and progressive disease (PD) were the most common outcomes, and the most frequent AEs were fatigue and diarrhea.

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