Beyond efficacy, new therapies like bispecifics require significant institutional support. Clinicians need training for unfamiliar side effects like CRS, and facilities need resources like observation units and admission protocols, creating a steep implementation curve for clinical practice.
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The future of advanced prostate cancer treatment may involve combining ADCs with bispecific T-cell engagers. This strategy could use ADCs for a short duration to deliver a potent hit, followed by immunotherapy to achieve durable remission, potentially reducing toxicity and enabling earlier use.
Unlike bladder cancer, prostate cancer has highly effective androgen-pathway inhibitors (ARPIs) that extend survival. This success has pushed chemotherapy and, by extension, ADC development to later treatment lines as clinicians prioritize other novel mechanisms of action first.
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.
For antibody-drug conjugates (ADCs) to make a meaningful impact in prostate cancer, the clinical development bar is exceptionally high. Merely showing activity in late-line settings is insufficient; the true measure of success is demonstrating superiority over the established chemotherapy standard, docetaxel.
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.
The rapid advancement of ARPIs wasn't just a scientific breakthrough. It was a rare convergence of FDA interest in new endpoints, a deeper biological understanding of castration resistance, and intense industry and academic collaboration that created a uniquely fertile ground for innovation.
In the AMPLITUDE trial, only 16% of high-risk metastatic prostate cancer patients received docetaxel, despite it being allowed and indicated by disease characteristics. This suggests a real-world "chemophobia" or physician bias towards newer targeted therapies, even within a clinical trial setting.
Three 2025 trials (AMPLITUDE, PSMA-addition, CAPItello) introduced personalized therapy for metastatic hormone-sensitive prostate cancer. However, significant benefits were confined to narrow subgroups, like BRCA-mutated patients. This suggests future success depends on even more stringent patient selection, not broader application of targeted agents.
While Lutetium shows promise in hormone-sensitive prostate cancer, experts raise concerns about potential late-effect toxicities for patients surviving many years. This contrasts with docetaxel, where toxicity is acute and resolves after treatment, highlighting an unknown long-term risk-benefit profile for new radioligand therapies.
An antibody-drug conjugate's (ADC) effectiveness is capped by its chemotherapy payload. In prostate cancer, topoisomerase inhibitors have a poor track record. Therefore, ADCs using this payload face an uphill battle compared to those with proven payloads like microtubule inhibitors (taxanes).