The NUS press release article does a great job of summing up the research findings and putting them into real world context. Of note, it is not just ZEN-3694 dose optimization, but also enzalutamide dose optimization, that is required for optimal combo synergy. Optimal dose finding for synergy/effectiveness in combo therapies is going to be a big hurdle. Not all patients are going to respond to the same dose(s); individualized dose regimens may be required. Artificial intelligence guided dose modifications use regularly monitored efficacy endpoints (such as weekly serum PSA levels here) from an individual patient to tailor the best doses of enzalutamide and ZEN-3694 to achieve the most robust and longest duration PSA response.  Not everyone has full access to the article, so for my benefit as well as everyone else's, here is my summary below. Quoted/italicized portions are directly lifted from the manuscript. The week numbers in my summary might not exactly line up because of some subjective interpretations of mine fromt the manuscript text vs. graph timeline.

In the article, they detail how CURATE.AI was used in one patient at UCLA in the ZEN-3694/enzalutamide mCRPC study. The first doses of enzalutamide and ZEN-3694 were 160 mg daily and 48 mg daily, respectively. During the first 6 months of combo treatment, doses were "physician-guided" without any AI input in order to generate PSA-response data for CURATE.AI program to learn from. PSA levels were measured weekly. Enzalutamide started at 160 mg daily, but was then cut back to 120 mg daily and then 80 mg daily at physician's discretion by week 6 of combo therapy due to patient reported outcomes and symptoms (e.g., fatigue, dysgeusia, loss of appetite, and weight loss). Within days of the enzalutamide dose reduction, the patient reported improved drug tolerability and decreased severity of drug related adverse events. ZEN-3694 was started at 48 mg daily but was cut back to 36 mg daily about 7 weeks into the combo period. "Following the dose reduction [from 48 mg to 36 mg daily), the physician adjusted the dosing schedule of ZEN-3694 from once daily to 5-2, in which the patient took 36 mg of ZEN-3694 once daily for 5 days, followed by 2 days off of ZEN-3694. The patient’s PSA level was observed to moderately increase from 2.4 to 5.4 ng mL−1 and eventually decrease to 0.91 ng mL−1 over a period of 16 weeks." For this 16 week period (ending at week 24 of combo period), enzalutamide was given at 80 mg daily and ZEN-3694 given at 36 mg on the 5-2 schedule. This concluded the "physican-guided" portion, at which point the patient's PSA level was 0.91 ng/mL.

The CURATE.AI-guided portion started at week 24. The physician decided that enzlutamide should be maintained at 80 mg daily, and then CURATE.AI recommended lowering ZEN-3694 from 36 mg once daily to 24 mg once daily "to simultaneously increase the treatment efficacy and tolerance." Weeks 24-26 were 24 mg once daily, which elicited a modest further PSA reduction to 0.86 ng/mL. From weeks 26 to 34 the physician changed to 24 mg on the 5-2 cycle, instead of once daily, which resulted in a further lowering of serum PSA levels to 0.68 ng/mL. The patient also reported improvement in his fatigue, appetite and weight gain during the period of switching from 36 mg to 24 mg ZEN-3694, so the physician (not CURATE.AI) reduced ZEN-3694 dose from 24 mg to 12 mg on the 5-2 schedule at week 34. CURATE.AI predicted that this would increase serum PSA to 1.52 ng/mL. What they actually observed was an increase in serum PSA from 0.68 ng/mL to 1.6 ng/mL during the 12-week period (weeks 34 to 48) while on the 12 mg dose. This new data was used to update the CURATE.AI profile for this patient. CURATE.AI recommended going back to 24 mg at week 50, which subsequently reduced serum PSA back down to 0.99 mg/dL by week 52. At week 58, the CURATE.AI recommended holding ZEN-3694 at 24 mg but increasing enzalutamide to 120 mg. CURATE.AI projected to this new combo to decrease the serum PSA level to 0.82 ng/mL and the subsequent measured serum PSA level was 0.78 ng/mL."The combination of 120 mg enzalutamide once daily and 24 mg ZEN-3694 on the 5-2 dosing schedule was continued for the following two weeks with corresponding PSA levels 0.78 and 0.87 ng/mL." At this point it was week 60 in the study and this was the end of the reported daata for this manuscript. 

One sentence from conclusion read "If predetermined and patient-specific dose expansion or escalation is initiated at the start of treatment, then CURATE.AI can potentially be implemented at an earlier time point." I wonder if all patients in the Phase 2 portion of the enzalutamide/ZEN-3694 combo mCRPC trial will have CURATE.AI informed dosing? Very exciting that Zenith's ZEN-3694 was chosen as the proof-of-principle example to use in this publication!

BearDownAZ