針對男性第二高發癌癥，這些療法正在為患者帶來新的曙光

編者按：前列腺癌是全球男性健康的重大威脅，根據2024年發表的全球癌癥統計數據，前列腺癌是男性中第二高發的癌癥類型，僅在2022年，全球就有超過146萬人確診，占所有癌癥新病例的7.3%。雖然早期篩查、手術和激素阻斷療法的進步顯著提高了早期患者的治愈率，但耐藥與復發問題依舊是晚期患者面臨的挑戰，在去勢抵抗性前列腺癌（CRPC）中尤為突出。針對這一難題，基于多種作用機制的創新療法已經進入臨床開發。長期以來，藥明康德通過“一體化、端到端”的CRDMO模式，持續支持不同類型前列腺癌創新療法的研發。本文將聚焦于克服前列腺癌耐藥性的前沿策略，并展示藥明康德在賦能新藥開發中的作用。

前列腺癌是一種依賴雄激素（如睪酮）驅動增殖的惡性腫瘤，早期往往無明顯癥狀，確診時常已進入局部晚期或轉移階段。20世紀中葉以前，診斷主要依賴癥狀及直腸指檢，早期發現率低，治療效果有限。直到20世紀80至90年代，前列腺特異性抗原（PSA）檢測的普及大幅提升了早期診斷率和治療機會，也顯著降低了患者的死亡率。

圖片來源：123RF

在治療方面，自20世紀40年代Charles Huggins博士與Clarence Hodges博士首次驗證睪丸切除術或雌激素對轉移性前列腺癌的療效以來，雄激素剝奪療法（ADT）便成為標準的系統治療之一。Huggins博士也因在前列腺癌激素療法上的貢獻，于1966年獲得諾貝爾生理學或醫學獎。隨著醫學發展，更溫和且可逆的治療方式陸續出現，包括促性腺激素釋放激素（GnRH）激動劑、拮抗劑及抗雄激素藥物，成為臨床治療的重要手段。這些療法能夠有效降低體內雄激素水平，從而抑制腫瘤進展。

然而，盡管ADT在短期內能夠控制病情，大多數患者最終仍會發展為CRPC。一旦癌細胞擺脫對雄激素的依賴，預后便會急劇惡化，使CRPC成為臨床上極具挑戰性的疾病階段。

聚焦“合成致死”機制

在治療前列腺癌的小分子研發管線中，研發人員嘗試的重要方向之一，是通過靶向AR以外的信號通路解決前列腺癌的耐藥性。其中，基于“合成致死”機制開發的多款創新療法已經獲得監管機構批準上市，例如，PARP抑制劑Rubraca（rucaparib）與Lynparza（olaparib）已經獲批用于治療攜帶

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新一代放療：放射性配體藥物

體外放射治療（EBRT）是治療早期前列腺癌的重要手段之一，但對于全身轉移的mCRPC患者，EBRT僅能緩解部分病灶，且存在損傷健康組織的風險。2013年，美國FDA批準了放射性療法Xofigo（Ra 223 dichloride），用于治療出現骨轉移的前列腺癌患者。其特性可模擬鈣元素，被快速增長的骨轉移瘤吸收，從而實現對骨轉移瘤的靶向殺傷。為了進一步提高放射性療法的精準性，研究人員開發了放射性配體藥物，通過將同位素與特異性配體結合，實現將放射性藥物精準遞送至腫瘤細胞，從而減少對正常組織的損害。

基于這一理念開發的Pluvicto（lutetium Lu 177 vipivotide tetraxetan）已獲FDA批準，用于治療前列腺特異性膜蛋白（PSMA）陽性的經治mCRPC患者。當前，全球已有40余款放射性配體藥物正在臨床階段探索治療前列腺癌的潛力，靶點主要為PSMA，還包括SSTR2、GRPR、DLL3、NTSR1、KLK2等。靶向配體形式涵蓋小分子、抗體與多肽，所用放射性同位素包括Lu 177、Ac 225、Ga 68、In 111等。

圖片來源：123RF

雖然放射性配體藥物在早期腫瘤成像和治療方面均展現巨大潛力，但其藥物結構復雜，通常由靶向配體、連接子、螯合劑和放射性同位素組成，其生產過程需要多學科的專業技術支持。藥明康德綜合性的放射性藥物發現平臺整合了多肽發現和放射性藥物開發能力，提供包括多肽合成、螯合劑合成、放射性標記、成像、藥理學研究和監管申報支持等完善的服務。一體化平臺讓多個團隊并行攻堅、高度協作，幫助合作伙伴快速推動項目進展，節省寶貴的開發時間。

靶向蛋白降解與誘導接近藥物

為了應對ADT耐藥性，研究者開發了多種靶向AR信號通路的創新策略。其中，靶向蛋白降解藥物（TPD）為克服傳統AR拮抗劑耐藥性帶來新希望。它們通過直接降解AR蛋白，可更深度、持久地抑制AR信號通路。例如，Arvinas公司開發的第二代AR靶向蛋白降解嵌合體（PROTAC?）ARV-766在早期臨床試驗中表現出能夠選擇性降解野生型和帶有臨床耐藥相關突變的AR的能力。諾華（Novartis）已與Arvinas達成超10億美元獨家許可協議，獲得該療法的全球開發和商業化權益。公開資料顯示，目前已有10多款TPD療法進入臨床階段，用于治療前列腺癌。

TPD之外，基于誘導接近（induced proximity）機制開發的調節誘導接近靶向嵌合體（RIPTAC）藥物HLD-0915也已經進入臨床。HLD-0915通過將AR與一個與轉錄調控相關的關鍵蛋白“綁”在一起，讓細胞啟動凋亡程序并死亡。在前列腺癌小鼠模型中，RIPTAC的表現已經優于多款獲批的AR拮抗劑和雄激素合成抑制劑。

在助力TPD療法從創新概念走向臨床驗證的過程中，藥明康德致力于支持全球客戶加速研發進程，憑借CRDMO平臺能夠“端到端”助力TPD分子從發現、到開發，再到生產交付的全過程。藥明康德已經助力70多種TPD分子進入臨床前候選藥物（PCC）階段，10多種已進入后期開發階段。

在上述介紹的療法類型之外，個體化癌癥疫苗以及雙特異性抗體等免疫療法也在前列腺癌臨床試驗中展現積極信號。

我們期待更多創新診療手段取得突破，為患者延長生命、提升治愈希望。未來，藥明康德將繼續依托其“一體化、端到端”的CRDMO模式，攜手全球合作伙伴，共同實現“讓天下沒有難做的藥，難治的病”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

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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.”

參考資料：

[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

免責聲明：本文僅作信息交流之目的，文中觀點不代表藥明康德立場，亦不代表藥明康德支持或反對文中觀點。本文也不是治療方案推薦。如需獲得治療方案指導，請前往正規醫院就診。

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