Much recent interest in Adaptive Therapy is a strategy of applied evolutionary dynamics to alternate two different treatments, or on-off cycles of one treatment, to provide stabilization between susceptible and resistant sub-populations of cancer cells to compete and stabilize populations for more prolonged survival with the disease. Bipolar Androgen Therapy (BAT) and similar are examples. As is the cycling of abiraterone/prednisone vs continuous. (Gatenby et al.)
jonsmitchell.com/biol461/fi...
A whole different level of "Evolutionary Dynamics" is present in approaches that use Extinctions Dynamics in treating cancer with the intention of "cure" (= extinction) through principles that lead to species extinctions in nature. Some of these have been well studied and documented. The principles are very applicable to metastatic prostate cancer, yet seldom seem to be employed in current clinical practice.
The approach is using a "First Strike" and "Second Strike". Two (or more) different therapies are applied in sequence, administered when the cancer population is most reduced and vulnerable, but before resistant cells can become predominant. An "extinction vortex" is a sequence of events that lead small populations to become increasingly more vulnerable as they spiral towards extinction.
This is the opposite of using a therapy (chemotherapy, ADT etc) at the maximum tolerated dosage (MDT) and continuing it even after maximum results: NED, "No evidence of Disease". In APC this is most often an undetectable PSA. Yet if the treatment is continued, it inevitably leads to recurrence of resistant disease. We know this all too well. First castrate resistant to ADT, then to subsequent agents over time.
Extinction theory would call for administering a second strike, a second and different treatment at exactly the time of reaching NED or treatment nadir. When ADT, of ADT plus an advanced AR drug succeed in reaching "undetectable PSA", would be the best time, not to continue monitoring for the inevitable recurrence of resistant disease. But to undertake aggressive taxane chemotherapy at that time. Then start a third treatment perhaps as soon as that is complete. (Might be such as immunotherapy, Lu-PSMA if avid mets are present, etc. as individual circumstances, genetics, co-morbidities, dictate the best choices).
Here is an article reviewing this topic as relates to cancer treatments. food for discussion with your medical teams. An excerpt follows.
cancerres.aacrjournals.org/...
Eradicating Metastatic Cancer and the Eco-Evolutionary Dynamics of Anthropocene Extinctions
Anthropocene extinctions suggest a strategy for eradicating metastatic cancers in which initial therapy, by reduc- ing the size and diversity of the population, renders it vulnerable to extinction by rapidly applied additional perturbations.
The evolutionary dynamics of Anthro- pocene extinctions suggest eradicating metastatic cancers may be possible through a strategic integration of several therapies, each of which, individually, cannot achieve a curative outcome and, in fact, may only be mildly effective.
This potential curative strategy requires two or more steps guided by eco-evolutionary principles. The first strike applies a therapy that is effective in reducing the population even though prior clinical experience has determined that it is rarely or never curative. The second strike, following immediately after the cancer cell population decline, exploits the unique properties of small populations. As generally seen in background extinctions, an identical perturbation may result in entirely different outcomes in small populations compared to large groups of the same species (17). This is due to the vulnerability of small populations to stochastic changes in birth and death rates (17), decreased cellular heterogeneity, and Allee effects that adversely affect small populations (19, 22).
Application of this strategy requires an initially effective first line treatment or sequence of treatments that can significantly reduce the cancer population ideally to NED, similar to standard first line therapy in current oncologic practice. Importantly, first-line treat- ment does not need to be a magic bullet that eradicates the entire cancer population. Rather, by significantly reducing the size and diversity of the cancer population, it renders it vulnerable to extinction. Effective first strikes are reasonably common. For exam- ple, androgen deprivation therapy for metastatic prostate cancer reduces PSA to normal or undetectable in >90% of patients. Similarly, initial chemotherapy for metastatic pediatric fusion- positive rhabdomyosarcoma (31, 32) and for small cell lung cancer renders most patients NED. However, clinical experience shows that curative outcomes are rare as small surviving resistant clones eventually repopulate the tumor.
Our proposed strategy differs from standard oncologic practice because it changes treatment even as the tumor is responding well to the first therapy. As demonstrated in Figs. 5 and 6, the standard practice of continued application of the same agent(s) at MTD therapy until tumor progression following an excellent initial response is ineffective because the surviving cancer cells are resistant. Further- more, during tumor growth from NED to measurable disease, the cancer population increases in both size and diversity. Thus, application of second line therapy is too late to produce extinction.
Thus, we hypothesized curative outcomes may be achievable if, after effective initial therapy, new treatments are applied immediately after achieving NED. Figures 5 through 7 are consistent with the hypothesis but also find the opportunity for extinction is broader than expected. In fact, consistent with the concept of the extinction vortex, cancers that remain sufficiently large to be observable but are in decline are also vulnerable to extinction from a second strike. In contrast, as shown in Figs. 6 and 7, combining the first- and second-strike agents at the initiation of therapy is ineffective. However, if applied within an optimal window of opportunity when the cancer population is small and in decline, simulations found that addition of an even mildly effective second agent (killing only 20% of the surviving cells) consistently resulted in extinction of the cancer population.
Dr. Sperling ECE article, not encouraging
Depression from 2nd-generation hormone therapy is worse
Update: FDA grants Priority Review for 177Lu-PSMA-617 for patients with metastatic castration-resistant
