The control arm in the EMBARK study was blinded to PSA results, preventing physicians from intervening with standard-of-care AR antagonists at PSA progression. This design likely delayed subsequent effective therapies, making the control arm underperform and potentially exaggerating the overall survival benefit of the experimental arms.
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The EMBARK trial showed that enzalutamide monotherapy was superior to standard ADT monotherapy for metastasis-free survival. This suggests potent AR antagonism may be a more effective strategy than simply depleting the testosterone ligand, challenging the long-held dogma of ADT being the fundamental building block for systemic prostate cancer therapy.
In trials like ASCENT-4, where over 80% of the control arm received sacituzumab govitecan upon progression, the true overall survival (OS) benefit is obscured. This makes progression-free survival (PFS) a more reliable endpoint for evaluating the drug's first-line efficacy.
The enzalutamide arms saw discontinuation rates of 20-25% due to adverse events. This high rate reflects a different risk calculation for patients who feel healthy and are asymptomatic. Unlike in advanced disease where patients tolerate more toxicity, this population has a very low threshold for side effects, making early intervention a significant trade-off.
The FDA's critique of both CREST and Potomac trials highlights that while event-free survival (EFS) endpoints were met, the lack of improvement in overall survival or prevention of muscle-invasive disease makes the risk/benefit profile questionable for an early-stage cancer, where treatment-related harm is a primary concern.
Developers often test novel agents in late-line settings because the control arm is weaker, increasing the statistical chance of success. However, this strategy may doom effective immunotherapies by testing them in biologically hostile, resistant tumors, masking their true potential.
The common practice of switching from one ARPI to another upon disease progression is now considered ineffective for most patients. With the advent of proven alternatives like chemotherapy and lutetium, using an "ARPI switch" as the sole control arm in clinical trials is no longer ethically or scientifically sound.
An overall survival (OS) benefit in an adjuvant trial may not be meaningful for patients in systems (e.g., the U.S.) with guaranteed access to the same effective immunotherapy upon recurrence. The crucial, unanswered question is whether treating micrometastatic disease is inherently superior to treating macroscopic disease later, a distinction current trial data doesn't clarify.
The EMBARK trial demonstrated an overall survival (OS) benefit, yet experts argue this doesn't automatically make treatment mandatory. For asymptomatic patients with a long life expectancy, factors like treatment-free survival and quality of life are critical considerations, challenging the primacy of OS as the sole decision-driver in this population.
A significant criticism of the pivotal KEYNOTE-564 trial is that only half the patients in the control arm received standard-of-care immunotherapy upon relapse. This lack of subsequent optimal treatment complicates the interpretation of the overall survival benefit, raising questions about its true magnitude.
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.