编者按：2024年美国临床肿瘤学会年会（ASCO 2024）已圆满落幕。在最新进展（LBA）报告中，约翰霍普金斯大学医学院Samuel R.Denmeade教授分享了TRANSFORMER试验的具体结果。TRANSFORMER是一项针对阿比特龙预处理转移性去势抵抗性前列腺癌（mCRPC）患者的随机试验，目的是在研究中确定是否可以识别出血液标志物。《肿瘤瞭望》有幸采访Samuel R.Denmeade教授，重点介绍了双极雄激素治疗（BAT）这一新疗法的潜在益处及未来方向。

 

Samuel R.Denmeade教授：当前治疗CRPC的方法非常复杂，最佳治疗顺序尚未明确。通常，我们首先采用激素疗法，这对大约三分之二的患者在短期内有效。然而，后续的治疗往往是非激素类的，且毒性更大，例如化疗和放疗。目前主要的未满足需求是开发能够延长前列腺癌激素敏感期的治疗方法，从而避免使用毒性更大的治疗。正是出于这一考虑，我们研究了BAT。

 

长期暴露于低水平激素会使癌症通过增加激素受体来适应，从而使其对高睾酮水平敏感。虽然给患者注射睾酮似乎与常规的阻断睾酮治疗相反，但我们发现相当多的男性对这种治疗有良好反应。他们通常感觉更强壮、更有精力，并且癌症对激素阻断疗法重新敏感。我们正在探索交替使用低激素和高激素的策略，以避免需要化疗。在美国，我们治疗了约300~400名患者，结果显示该疗法是安全的，并且有良好的反应率。许多患者对激素阻断疗法重新敏感，而且这种治疗非常经济。我们对其作为标准治疗的潜力感到兴奋。

 

Oncology Frontier:What unmet treatment needs do you think exist for mCRPC patients?

 

Dr.Samuel R.Denmeade:The treatment of prostate cancer when it becomes castrate-resistant is complex，and the best sequence of treatments is not entirely clear.Initially，we often use hormone therapy，which can be effective for a short period in about two-thirds of patients.However，subsequent treatments tend to be non-hormonal and more toxic，such as chemotherapy and radiation therapies.The significant unmet need is to develop treatments that can prolong the hormone-sensitive phase of prostate cancer and avoid more toxic treatments.This is where our research on bipolar androgen therapy comes in.

 

Prolonging exposure to low hormone levels makes the cancer adapt by increasing the hormone receptor，paradoxically making it sensitive to high testosterone.While it may seem counterintuitive to give testosterone，as most treatments aim to block it，we found that a significant number of men respond well to this treatment.They generally feel stronger and have more energy，and the cancer becomes re-sensitized to hormone-blocking treatments.We’re exploring a strategy of alternating low and high hormone levels to avoid the need for chemotherapy.

 

We have treated about 300 to 400 patients in the U.S.，and it appears to be safe with a good response rate.Many patients show re-sensitization to hormone-blocking treatments，and it’s also an inexpensive treatment.We’re excited about its potential as a standard treatment.

 

Samuel R.Denmeade教授：在我们的研究中，我们观察到雄激素受体水平较高的癌症患者往往对BAT反应更好。我们正致力于通过检测循环肿瘤DNA来评估血液中的雄激素受体水平，这比侵入性活检更为简便。

 

研究表明，高水平的雄激素受体与更好的治疗反应相关。因此理想情况下，CPRC患者可以抽血检测这一生物标志物。如果标志物水平高，我们会考虑BAT。若标志物水平低，我们可能会继续标准的激素治疗。这一策略有助于我们为患者制定更个性化的治疗方案，提高疗效。

 

Oncology Frontier:Can blood-based markers be used to identify patients who are effectively treated with bipolar androgen therapy?

 

Dr.Samuel R.Denmeade:In our studies，we found that patients with high levels of the androgen receptor tend to respond better.Instead of invasive biopsies，we’re exploring measuring the receptor levels in the blood using circulating tumor DNA.

 

High levels of the androgen receptor correlate with better responses to the therapy.Ideally，a patient with resistant prostate cancer would have their blood drawn to check for this marker.If the marker is high，we would consider bipolar androgen therapy.If it’s low，we might continue with standard hormone treatment.This could help tailor treatment decisions and improve outcomes.

 

Samuel R.Denmeade教授：我们希望将BAT确立为标准治疗。未来的研究将集中于将新疗法，如双特异性抗体、抗体-药物偶联物（ADC）以及新的细胞疗法，与BAT联合，以进一步改善疗效。我们希望生物标志物能帮助我们识别最有可能从这种治疗中受益的患者，使治疗更有效、更个性化。

 

Oncology Frontier:What are the implications of these findings for the treatment of prostate cancer?How should they be applied in clinical practice?

 

Dr.Samuel R.Denmeade:We aim to establish this as a standard treatment.Future research will focus on integrating new modalities，such as bispecific antibodies，antibody-drug conjugates，and new cellular therapies，with bipolar androgen therapy to further enhance patient outcomes.We hope the marker will help us identify patients most likely to benefit from this treatment，making it more effective and personalized.