Injectable testosterone suppresses natural production, causing infertility. New protocols use shorter-half-life oral/topical testosterone combined with enclomiphene (which blocks estrogen feedback) to increase T-levels while maintaining the body's own production, making it a viable option for younger men concerned about fertility.

The PRESTO trial evaluated adding apalutamide (APA) and abiraterone (Abby) to a standard LHRH analog. The triplet combination arm demonstrated increased toxicity without any additional efficacy gains compared to the doublet arm (LHRH + APA). This finding reinforces that more intensive combination therapy is not always better and can be detrimental in this setting.

The selection between PARP inhibitors like olaparib and niraparib is not one-size-fits-all. It's a personalized decision based on patient preference for dosing frequency (once vs. twice daily), tolerance for side effects like hypertension, and potential drug-drug interactions.

To determine if fatigue or cognitive dysfunction is caused by enzalutamide, a clinician suggests a practical approach called the "Stevens Maneuver." The patient stops the drug for two weeks. If symptoms don't improve, the cause is likely something else. If they do improve, the drug is the culprit, and it can often be resumed at a lower dose.

If lutetium-PSMA is approved and used upfront in hormone-sensitive disease, clinicians may become more comfortable with radioligands generally. This could lead them to use the enzalutamide-radium combination more frequently later on, paradoxically increasing radium's use by flipping the current treatment sequence.

Even when an ARPI is no longer effective as a standalone therapy, continuing it may be beneficial. By maintaining pressure on the androgen receptor pathway, the drug can upregulate downstream targets like PSMA, potentially enhancing the efficacy of subsequent PSMA-targeted therapies like radioligands or ADCs.

The failure of Roche's gerodestrant when combined with a CDK4/6 inhibitor suggests these oral SERDs may not add benefit to that backbone. This contrasts with its success alone in an adjuvant setting, reframing the drugs as an "either-or" choice rather than a combination therapy in the first-line setting.

An ESR1 mutation locks the estrogen receptor in a permanently "on" state, independent of estrogen. This renders aromatase inhibitors (AIs) ineffective but means therapies that degrade the receptor itself, like SERDs, can still be effective treatment options.

Clinical trials combining potent ARPIs like abiraterone and enzalutamide have consistently failed. Once the androgen receptor pathway is maximally suppressed by one agent, adding another with a similar mechanism provides no further clinical advantage, much like hammering a nail that is already flush with the wood.