The negative ANSA-RAD trial, when contrasted with the positive STAMPEDE trial, demonstrates that patient selection is paramount in adjuvant therapy. The difference in outcomes was driven by risk definition, not the drug. This reinforces that "negative" trials are clinically vital for defining which patient populations do not benefit, preventing widespread overtreatment.

The effectiveness of radioligand therapy is counterintuitive: as tumors shrink and PSMA binding sites decrease, less radiation is delivered to the cancer. The VISION trial showed the first two doses delivered more radiation to the tumor than the subsequent four, questioning the value of a fixed, prolonged treatment schedule.

The investigator-led PLUTO trial found docetaxel chemotherapy provided a better overall survival benefit than lutetium in first-line mCRPC. This result directly confronts the common clinical bias against chemotherapy ("chemophobia"), proving that older treatments can still outperform newer targeted agents and should not be prematurely abandoned.

A key hypothesis for why docetaxel showed better overall survival than lutetium in the PLUTO trial is that patients treated with lutetium upfront may become unfit for subsequent chemotherapy. This highlights a critical factor in trial design: the planned therapeutic sequence and a patient's ability to receive later-line treatments significantly impact survival outcomes.

Radioligand therapy has a unique toxicity profile, described as 'the gift that keeps on giving,' where side effects can worsen even after the treatment course is complete. This contrasts with chemotherapy like docetaxel, where a patient's quality of life often rebounds and improves once the drug is stopped.

Lutetium faces criticism for its fixed 6-cycle regimen, which may be suboptimal as the PSMA target diminishes with ADT. However, this critique is rarely applied to other drugs like PARP inhibitors, which are given until progression. This highlights a double standard and the tension between using a fixed regimen for regulatory approval versus finding the optimal dose in practice.

With highly active agents yielding 30% complete response rates, the immediate goal should be to cure more patients by exploring potent combinations upfront. While sequencing minimizes toxicity, an ambitious combination strategy, such as ADC doublets, offers the best chance to eradicate disease and should be prioritized in clinical trials.

Actuate employed a master protocol that tested their drug alongside eight different standard-of-care chemotherapies in patients who had already failed them. This design efficiently demonstrated the drug's ability to reverse chemo-resistance across multiple histologies, informing their Phase 2 strategy.

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.