编者按：前列腺癌是全球男性健康的重大威胁，根据2024年发表的全球癌症统计数据，前列腺癌是男性中第二高发的癌症类型，仅在2022年，全球就有超过146万人确诊，占所有癌症新病例的7.3%。虽然早期筛查、手术和激素阻断疗法的进步显著提高了早期患者的治愈率，但耐药与复发问题依旧是晚期患者面临的挑战，在去势抵抗性前列腺癌（CRPC）中尤为突出。针对这一难题，基于多种作用机制的创新疗法已经进入临床开发。长期以来，药明康德通过“一体化、端到端”的CRDMO模式，持续支持不同类型前列腺癌创新疗法的研发。本文将聚焦于克服前列腺癌耐药性的前沿策略，并展示药明康德在赋能新药开发中的作用。
前列腺癌是一种依赖雄激素（如睾酮）驱动增殖的恶性肿瘤，早期往往无明显症状，确诊时常已进入局部晚期或转移阶段。20世纪中叶以前，诊断主要依赖症状及直肠指检，早期发现率低，治疗效果有限。直到20世纪80至90年代，前列腺特异性抗原（PSA）检测的普及大幅提升了早期诊断率和治疗机会，也显著降低了患者的死亡率。
在治疗方面，自20世纪40年代Charles Huggins博士与Clarence Hodges博士首次验证睾丸切除术或雌激素对转移性前列腺癌的疗效以来，雄激素剥夺疗法（ADT）便成为标准的系统治疗之一。Huggins博士也因在前列腺癌激素疗法上的贡献，于1966年获得诺贝尔生理学或医学奖。随着医学发展，更温和且可逆的治疗方式陆续出现，包括促性腺激素释放激素（GnRH）激动剂、拮抗剂及抗雄激素药物，成为临床治疗的重要手段。这些疗法能够有效降低体内雄激素水平，从而抑制肿瘤进展。
然而，尽管ADT在短期内能够控制病情，大多数患者最终仍会发展为CRPC。一旦癌细胞摆脱对雄激素的依赖，预后便会急剧恶化，使CRPC成为临床上极具挑战性的疾病阶段。
聚焦“合成致死”机制
在治疗前列腺癌的小分子研发管线中，研发人员尝试的重要方向之一，是通过靶向AR以外的信号通路解决前列腺癌的耐药性。其中，基于“合成致死”机制开发的多款创新疗法已经获得监管机构批准上市，例如，PARP抑制剂Rubraca（rucaparib）与Lynparza（olaparib）已经获批用于治疗携带BRCA突变或同源重组修复（HRR）缺陷的转移性去势抵抗性前列腺癌（mCRPC）患者。Talzenna（talazoparib）则获批与Xtandi（enzalutamide）联合使用，用于治疗HRR突变的mCRPC患者。Akeega（niraparib/abiraterone acetate）也获FDA批准治疗BRCA阳性mCRPC。此外，研发管线中约40款新药聚焦于合成致死机制，靶点涵盖PARP、EZH2、ATR、PLK1、POLQ、USP1、PRMT5等。
新一代放疗：放射性配体药物
体外放射治疗（EBRT）是治疗早期前列腺癌的重要手段之一，但对于全身转移的mCRPC患者，EBRT仅能缓解部分病灶，且存在损伤健康组织的风险。2013年，美国FDA批准了放射性疗法Xofigo（Ra 223 dichloride），用于治疗出现骨转移的前列腺癌患者。其特性可模拟钙元素，被快速增长的骨转移瘤吸收，从而实现对骨转移瘤的靶向杀伤。为了进一步提高放射性疗法的精准性，研究人员开发了放射性配体药物，通过将同位素与特异性配体结合，实现将放射性药物精准递送至肿瘤细胞，从而减少对正常组织的损害。
基于这一理念开发的Pluvicto（lutetium Lu 177 vipivotide tetraxetan）已获FDA批准，用于治疗前列腺特异性膜蛋白（PSMA）阳性的经治mCRPC患者。当前，全球已有40余款放射性配体药物正在临床阶段探索治疗前列腺癌的潜力，靶点主要为PSMA，还包括SSTR2、GRPR、DLL3、NTSR1、KLK2等。靶向配体形式涵盖小分子、抗体与多肽，所用放射性同位素包括Lu 177、Ac 225、Ga 68、In 111等。
图片来源：123RF
虽然放射性配体药物在早期肿瘤成像和治疗方面均展现巨大潜力，但其药物结构复杂，通常由靶向配体、连接子、螯合剂和放射性同位素组成，其生产过程需要多学科的专业技术支持。药明康德综合性的放射性药物发现平台整合了多肽发现和放射性药物开发能力，提供包括多肽合成、螯合剂合成、放射性标记、成像、药理学研究和监管申报支持等完善的服务。一体化平台让多个团队并行攻坚、高度协作，帮助合作伙伴快速推动项目进展，节省宝贵的开发时间。
靶向蛋白降解与诱导接近药物
为了应对ADT耐药性，研究者开发了多种靶向AR信号通路的创新策略。其中，靶向蛋白降解药物（TPD）为克服传统AR拮抗剂耐药性带来新希望。它们通过直接降解AR蛋白，可更深度、持久地抑制AR信号通路。例如，Arvinas公司开发的第二代AR靶向蛋白降解嵌合体（PROTAC®）ARV-766在早期临床试验中表现出能够选择性降解野生型和带有临床耐药相关突变的AR的能力。诺华（Novartis）已与Arvinas达成超10亿美元独家许可协议，获得该疗法的全球开发和商业化权益。公开资料显示，目前已有10多款TPD疗法进入临床阶段，用于治疗前列腺癌。
TPD之外，基于诱导接近（induced proximity）机制开发的调节诱导接近靶向嵌合体（RIPTAC）药物HLD-0915也已经进入临床。HLD-0915通过将AR与一个与转录调控相关的关键蛋白“绑”在一起，让细胞启动凋亡程序并死亡。在前列腺癌小鼠模型中，RIPTAC的表现已经优于多款获批的AR拮抗剂和雄激素合成抑制剂。
在助力TPD疗法从创新概念走向临床验证的过程中，药明康德致力于支持全球客户加速研发进程，凭借CRDMO平台能够“端到端”助力TPD分子从发现、到开发，再到生产交付的全过程。药明康德已经助力70多种TPD分子进入临床前候选药物（PCC）阶段，10多种已进入后期开发阶段。
在上述介绍的疗法类型之外，个体化癌症疫苗以及双特异性抗体等免疫疗法也在前列腺癌临床试验中展现积极信号。我们期待更多创新诊疗手段取得突破，为患者延长生命、提升治愈希望。未来，药明康德将继续依托其“一体化、端到端”的CRDMO模式，携手全球合作伙伴，共同实现“让天下没有难做的药，难治的病”的愿景。
Shedding Light on the Second Most Common Cancer in Men: Hundreds of Investigational Drugs Are Bringing New Hope
September is Prostate Cancer Awareness Month. Prostate cancer remains a major threat to men’s health worldwide. According to the global cancer statistics published in 2024, it is the second most common cancer among men, with more than 1.46 million new cases diagnosed in 2022 alone—accounting for 7.3% of all new cancer cases. Advances in early screening, surgery, and hormone-blocking therapies have significantly improved cure rates for patients diagnosed at an early stage. Yet for those with advanced disease, resistance and relapse remain formidable challenges, particularly in castration-resistant prostate cancer (CRPC). To address these unmet needs, innovative therapies based on diverse mechanisms of action are progressing through clinical development. WuXi AppTec has long supported the development of such therapies through its fully integrated, end-to-end CRDMO services. This article explores the forefront of treatment strategies aimed at overcoming resistance in prostate cancer and highlights WuXi AppTec’s role in enabling new drug innovation.
Prostate cancer is an androgen-dependent malignancy, typically driven by hormones such as testosterone. In its early stages, it often presents without obvious symptoms, and many cases are diagnosed only once the disease has progressed to locally advanced or metastatic stages. Prior to the mid-20th century, diagnosis relied largely on symptoms and digital rectal examination, leading to low detection rates and poor treatment outcomes. The introduction and widespread adoption of prostate-specific antigen (PSA) testing during the 1980s and 1990s marked a turning point, dramatically increasing early detection and treatment opportunities while significantly reducing mortality.
On the therapeutic front, androgen deprivation therapy (ADT) has been the cornerstone of systemic treatment since the 1940s, when Dr. Charles Huggins and Dr. Clarence Hodges first demonstrated that orchiectomy or estrogen could effectively treat metastatic prostate cancer. For his groundbreaking contributions, Dr. Huggins was awarded the Nobel Prize in Physiology or Medicine in 1966. As medical science advanced, less invasive and reversible approaches—including gonadotropin-releasing hormone (GnRH) agonists, antagonists, and antiandrogens—were introduced, offering more options to suppress androgen production and inhibit tumor growth.
Despite these advances, most patients eventually progress to CRPC. Once cancer cells escape androgen dependence, prognosis worsens dramatically, making CRPC one of the most difficult stages of the disease to manage. This urgent clinical challenge has spurred the development of next-generation therapeutic strategies.
Harnessing the Power of Synthetic Lethality
Beyond AR signaling, researchers are exploring alternative pathways to overcome resistance. One of the most successful approaches has been the use of synthetic lethality. Several therapies developed on this principle have already received regulatory approval. For example, the PARP inhibitors Rubraca (rucaparib) and Lynparza (olaparib) have been approved for patients with BRCA mutations or homologous recombination repair (HRR) deficiencies in metastatic CRPC. Talzenna (talazoparib) can be used in combination with the hormone therapy drug enzalutamide to treat metastatic CRPC patients with HRR mutations. More recently, Akeega (niraparib and abiraterone acetate) was approved by the FDA for BRCA-positive mCRPC.
The pipeline remains rich, with around 40 investigational drugs under development targeting synthetic lethality mechanisms, including PARP, EZH2, ATR, PLK1, POLQ, USP1, and PRMT5.
Emerging synthetic lethality targets are also gaining momentum. PRMT5 inhibitors have shown the ability to selectively kill MTAP-deleted tumor cells, while WRN inhibitors are being studied in tumors with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).
Next-Generation Radiotherapy: Radioligand Therapies
External beam radiation therapy (EBRT) has long been a mainstay for early-stage prostate cancer, but for patients with metastatic CRPC, EBRT is limited to treating only a few lesions and carries the risk of collateral damage to healthy tissue. In 2013, the U.S. FDA approved the radiopharmaceutical Xofigo (Ra 223 dichloride) for the treatment of prostate cancer patients with bone metastases. The drug mimics calcium, allowing it to be absorbed by rapidly growing bone metastases and exerting a targeted killing effect. In addition, radioligand therapies (RLTs) are emerging as a more precise alternative. By linking isotopes to tumor-targeting ligands, RLTs deliver radiation directly to cancer cells while sparing normal tissue.
Pluvicto (lutetium Lu 177 vipivotide tetraxetan) is a leading example of this approach. Approved by the FDA for PSMA-positive, previously treated mCRPC patients, Pluvicto has demonstrated meaningful clinical benefit. Globally, more than 40 radioligand therapies are in clinical development for prostate cancer, most targeting PSMA but also receptors such as SSTR2, GRPR, DLL3, NTSR1, and KLK2. Ligands range from small molecules to antibodies and peptides, while isotopes include Lu 177, Ac 225, Ga 68, and In 111.
The complexity of RLTs, which typically consist of a ligand, linker, chelator, and radioactive isotope, requires highly specialized, multidisciplinary expertise. WuXi AppTec’s integrated radiopharmaceutical discovery platform combines peptide discovery with radiopharmaceutical development, offering services from peptide and chelator synthesis to radiolabeling, imaging, pharmacology, and regulatory submission support. This one-stop approach allows multiple teams to collaborate in parallel, accelerating timelines and conserving valuable development resources.
Targeted Protein Degradation and Induced Proximity Therapies
To combat ADT resistance, researchers are exploring new therapeutic strategies to target the AR signaling pathway. Among the most promising is targeted protein degradation (TPD), which offers a way to overcome resistance to conventional AR antagonists. By directly degrading AR proteins, TPD therapies can achieve deeper and more durable inhibition of AR signaling. A leading example is an AR-targeting PROTAC® ARV-766, which in early clinical trials has demonstrated the ability to selectively degrade both wild-type AR and resistant AR mutants. Public data indicate that more than 10 TPD therapies are currently in clinical development for prostate cancer.
Another innovative approach is induced proximity–based therapies. HLD-0915, a regulated induced proximity targeting chimera (RIPTAC) molecule now in clinical trials for metastatic CRPC, forces AR to interact with a key transcriptional regulator, triggering apoptosis and tumor cell death. In preclinical mouse models, RIPTACs have outperformed several approved AR antagonists and androgen synthesis inhibitors.
WuXi AppTec is actively enabling the transition of TPD therapies from concept to clinic. Through its CRDMO platform, the company provides end-to-end support—from discovery and development through to manufacturing—helping accelerate progress. To date, WuXi AppTec has supported the advancement of more than 70 TPD molecules into preclinical candidate (PCC) stage, with over 10 advancing to late-stage development.
Looking Ahead
In addition to these therapeutic strategies, personalized cancer vaccines and novel immunotherapies such as bispecific antibodies are also showing promise in prostate cancer clinical trials. During this Prostate Cancer Awareness Month, we look forward to continued breakthroughs that extend survival and improve the chance of cure for patients. Looking to the future, WuXi AppTec will continue to leverage its fully integrated, end-to-end CRDMO model to accelerate innovation with global partners, advancing toward the shared vision that “Every drug can be made and every disease can be treated.”
参考资料（可上下滑动查看）
[1] State of the art — biomarkers in advanced prostate cancer. Retrieved August 20, 2025, from https://www.nature.com/articles/s41585-025-01080-0
[2] Denmeade & Isaacs (2002). A history of prostate cancer treatment. Nat Rev Cancer., doi: 10.1038/nrc801
[3] Lehtonen & Kellokumpu-Lehtinen (2023). The past and present of prostate cancer and its treatment and diagnostics: A historical review. SAGE Open Med., doi: 10.1177/20503121231216837.
[4] U.S. FDA Approves AKEEGA™ (Niraparib and Abiraterone Acetate), the First-And-Only Dual Action Tablet for the Treatment of Patients with BRCA-Positive Metastatic Castration-Resistant Prostate Cancer. Retrieved August 21, 2025, from https://www.jnj.com/media-center/press-releases/u-s-fda-approves-akeega-niraparib-and-abiraterone-acetate-the-first-and-only-dual-action-tablet-for-the-treatment-of-patients-with-brca-positive-metastatic-castration-resistant-prostate-cancer
[5] Bray et al., (2024). Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, https://doi.org/10.3322/caac.21834
[6] Zhang et al., (2025). A review of the efficacy of prostate cancer therapies against castration-resistant prostate cancer. Drug Discovery Today, https://doi.org/10.1016/j.drudis.2025.104384
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