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There is long-term data showing that adding hormone therapy to radiation can be curative for some prostate cancer patients. However, for surgery, historical and recent trials like PROTEUS have not demonstrated that perioperative hormone therapy adds a curative benefit, suggesting its role is more cytostatic in that context.
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Unlike in breast or bladder cancer, the significant improvement in pathologic response in the PROTEUS trial did not translate to a similarly impressive benefit in metastasis-free survival. This disconnect suggests that eliminating tumor in the prostate specimen is not a reliable surrogate for long-term outcomes in this disease setting.
A meta-analysis of six trials (Poseidon) found no overall survival benefit from adding long-course (24 months) hormone therapy to post-operative radiotherapy. It suggests that a shorter course of 4-6 months is adequate for most men, marking a significant shift towards treatment de-escalation to reduce long-term toxicity without compromising efficacy in this specific setting.
The PROTEUS trial used ADT plus surgery as its control, not surgery alone. This design is controversial because many patients choose surgery specifically to avoid systemic therapies like ADT. This complicates the interpretation of results and reflects a disconnect from real-world patient motivations.
Shifting the view of prostate cancer from "androgen-driven" to "androgen receptor-driven" provides a new framework. In curative settings, after the androgen receptor is targeted for a defined period, restoring testosterone is seen as logical to improve patient quality of life once the cancer is destroyed.
The standard practice of using rising PSA to trigger early salvage radiotherapy after surgery is complicated by the PROTEUS protocol's neoadjuvant hormone therapy. This approach muddies the interpretation of biochemical recurrence, making it difficult for clinicians to know when or if to intervene with salvage treatment, potentially leading to worse outcomes.
After years of successfully intensifying hormonal therapy, the focus in prostate cancer is shifting toward de-intensification. Researchers are exploring intermittent therapy for top responders and developing non-hormonal approaches like radioligands to spare patients the chronic, life-altering side effects of permanent castration.
Early neoadjuvant trials in the 1990s failed to show clinical benefit because they included many low-risk patients and used less potent hormonal therapies. The PROTEUS trial's success was built on learning from this history by strictly enrolling high-risk patients and using a powerful androgen receptor pathway inhibitor (ARPI).
The term "hormone resistance" was misleading. Researchers discovered that even in a castrate state, prostate cancer tumors produce their own testosterone locally. This maintained androgen receptor signaling, proving the disease was still "androgen addicted" and opening the door for new targeted therapies.
Johnson & Johnson's data for its drug Erlita doesn't just offer an incremental improvement; it challenges the century-old practice of immediate radical prostatectomy for high-risk prostate cancer. Integrating pharmaceutical treatment before and after surgery could fundamentally shift the treatment paradigm from a purely surgical approach to a multidisciplinary one.
The IMbark trial demonstrated that an ARPI (enzalutamide), either alone or with ADT, outperformed ADT monotherapy in high-risk patients. This pivotal finding raises the question of whether giving ADT alone in any setting, such as with radiation for localized disease, is now an outdated and inferior approach.