New study below [1].
Why would anyone even try to understand what these guys were trying to do, given the title? Here's why:
a) "Abiraterone treats metastatic castrate-resistant prostate cancer by inhibiting CYP17A, an enzyme for testosterone auto-production. With standard dosing, evolution of resistance with treatment failure (radiographic progression) occurs at a median of ~16.5 months."
b) "Adaptive therapy, using patient-specific tumor dynamics to inform on/off treatment cycles, suppresses proliferation of androgen-independent cells and lowers cumulative drug dose. In a pilot clinical trial, 10 of 11 patients maintained stable oscillations of tumor burdens; median TTP is at least 27 months with reduced cumulative drug use of 47% of standard dosing." (at the time of writing, the median had not been reached)
Instead of blindly following the shortest path from Zytiga-naive to Zytiga-resistant PCa, interrupt treatment at key points so as to reset the clock, if you will. Repeat as many times as you can.
The model recognizes three classes of cells:
"(i) testosterone-positive cells requiring exogenous androgen
"(ii) cells expressing CYP17A1 and producing testosterone
"(iii) testosterone-negative cells that are androgen-independent and resistant to abiraterone"
"At the time of writing, 11 patients (Table 2) have been on the trial sufficiently long (>10 months) to be compared with a contemporaneous cohort and historic controls. As predicted by the mathematical models, cycles of PSA were observed (Fig. 4) with cycle lengths ranging from 3 months to >1 year. Four patients have completed two adaptive cycles and all four patients achieved > 50% decline of PSA when abiraterone was restarted at cycle 3 (primary end point). The current clinical status of the trial cohort is shown in Fig. 5. One patient developed PSA and radiographic progression at month 11. Two patients have exhibited PSA progression at 21 and 28 months but remain on trial with no radiographic progression. Two patients declined to continue GnRH suppression with Leuprolide (an ADT that is continuously administered as part of any abiraterone therapy) at months 17 and 20, respectively, but continue taking abiraterone. None of the 11 patients have experienced grade 2 or above adverse events that would necessitate stopping abiraterone and prednisone."
"Also notable is the reduction in cumulative drug dose. Because of the on/off cycling of abiraterone, the adaptive therapy cohort has received an average cumulative dose of just 47% compared to continuous dosing used in standard of care (Fig. 5; Table 2). Three of the 11 patients have received < 25% of the cumulative SOC dose."
"Our adaptive therapy cohort has not reached a median time to either PSA or radiographic progression but, at the time of submission, they can be no less than 27 months."
The mathematics are beyond me & I don't follow how treatment is tailored to the individual, but the basic idea is clear.
Note that intermittent ADT [IADT] is not "adaptive", since testosterone [T] takes many months to recover, & rarely to the previous high, which is often close the hypogonadal cut-off anyway. Castration continues well into the off-phase, according to Freedland. In addition, the first on-phase is often a year, by which time only "bad" cells are present. If T were to be supplemented in the off phase-of IADT, after a much shorter on-phase, we would expect to see some reset activity.
In Denmeade's BAT (bipolar androgen therapy) study at Johns Hopkins, a high dose of T is given once a month. Cells never really get a chance to adapt to castrate T levels.
The new study does nothing as dramatic as restoring T. Treatment was interrupted on the basis that undesirable cells would be at a disadvantage:
"Thus, appropriately timed withdrawal of treatment can allow residual populations of sensitive cells to exploit their fitness advantage at the expense of the less-fit resistant phenotypes." (The key is to not kill the sensitive cells up front.)
Imagine if T were to be introduced to help things along?
-Patrick
[1] nature.com/articles/s41467-... (Full text)
