ncbi.nlm.nih.gov/pmc/articl...
Results
A total of 21 asymptomatic patients with mCRPC were included. There was a median of two lines before BAT, with nine patients (42.8%) receiving three or more lines, and 13 patients (61.9%) receiving chemotherapy previously. Previous lines included next-generation hormonal agents (NHA) in 100% (abiraterone 33.3% and enzalutamide 71.4%), chemotherapy in 61.9%, Radium-223 in 47.6% and others in 4.8%. The progression free survival (PFS) after BAT was 3.5 months (95% CI: 3.06–7.97). PSA50 response rate (RR) was 28.5% and the overall RR was 14.3%. Of the 17 patients who had disease progression, 9 had a rechallenge to NHA, achieving a 55% RR, 6 received other treatment (chemotherapy in 5 and 177Lu-PSMA in 1) with a 66% RR and 2 best supportive care. The PFS2, calculated after the initiation of BAT in the 15 patients who received further therapy, was 7.93 months (95% CI: 6.73–NR). Treatment was overall well tolerated, with only two patients requiring hospitalisation and treatment interruption due to worsening pain.
Conclusion
To the authors’ knowledge, this is the first publication of BAT in later lines of therapy in mCRPC. BAT showed clinical activity in this scenario. Our data supports that BAT may play a role in CRPC re-sensitisation after multiple treatment lines.
Discussion
Several trials and a systematic review have tried to demonstrate the efficacy of BAT in patients with mCRPC, especially its effects in the re-sensitisation to hormonal therapy, but none of these trials tested BAT in heavily pretreated patients or in patients with previous use of chemotherapy. A randomised multicentre phase II trial comparing BAT versus enzalutamide in 195 men with CRPC progressed to abiraterone showed similar clinical/radiographic PFS and PSA50 in both arms, with longer biochemical PFS with BAT. Interestingly, the PSA-PFS for enzalutamide increased from 3.8 months after abiraterone to 10.9 months after BAT, and PFS2 with BAT followed by enzalutamide was significantly longer than with enzalutamide followed by BAT, proving the hypothesis that BAT can re-sensitise CRPC to subsequent antiandrogen therapy [17].
Another phase II multi cohort trial evaluated BAT in men with metastatic and non-metastatic CRPC. Two cohorts evaluated whether BAT could restore sensitivity to abiraterone and enzalutamide by treating patients who previously failed to one of these therapies with BAT and then subsequent retreatment with abiraterone or enzalutamide. In the enzalutamide cohort, a 50% decrease in PSA (PSA50) was observed in 30% of patients when treated with BAT, and 52% had a PSA response when retreated with enzalutamide. In the abiraterone cohort, PSA50 was 17% and only 16% had PSA response in retreatment [18, 19]. Finally, in the report of the cohort examining BAT as a first-line hormonal treatment for metastatic CRPC (patients not exposed to AR-targeted therapies), BAT was well tolerated and resulted in prolonged disease stabilisation, with favourable responses to subsequent second-generation AR-targeted therapies [20].
Several limitations of this analysis should be addressed. Small number of patients and a retrospective, non-randomised study limit the interpretation of data. Also, the heterogeneous population included and without a uniform indication for BAT. Even though, we observed a similar RR with enzalutamide re-challenge as in the Teply et al [18] trial and a slightly shorter PFS2 compared to Denmeade et al [17] trial. These findings support the hypothesis that BAT can re-sensitise prostate cancer cells to enzalutamide, even after several lines of treatment, and raise the question to whether BAT should be offered to these patients. mCRPC patients have limited options after becoming resistant to new hormonal agents. Usually, we use chemotherapy and/or radiopharmaceutical agents such as radium-223 or 177Lu-PSMA. These treatments should be offered to our patients because they have showed survival advantage in randomised phase 3 clinical trials, but in many instances, patients progress to all these available treatments and had no other options, been BAT the option.
In Latin America countries as well in lower or lower-middle income countries, access to this newer treatment is not always universal so we have to consider lines of treatment that are accessible in matter of costs and taking into account improvement of quality of life and prolonging hormonal sensitivity.
Among the advantages of using BAT, is the good tolerance to treatment, and this makes its combination with different agents such as new hormonal agents or immunotherapy feasible. To highlight, we mention the study by Markowski et al[31] where patients who received BAT and were then exposed to immunotherapy experienced 100% decreases in PSA and one patient remained in long-term remission turning this strategy into a hypothesis to be studied in future trials.Go to:
Conclusion
These results were not enough to change practice in these institutions, but more physicians seem more prone to its use, especially for patients in which the effects of androgen deprivation greatly affect their quality of life, or for patients not suitable for chemotherapy. We encourage medical oncologist to discuss all these patients into a multidisciplinary tumour board.
There is still much to learn about this strategy, and more efforts should be put in prospective trials to test these findings. Until now, the only clear criterion to use BAT is in asymptomatic patients (due to the probability of worsening pain secondary to a flare effect), and perhaps a more detailed evaluation of biomarkers could help to better select patients. In addition, we believe that quality of life and cost-effectiveness studies are also necessary (even though this was not tested in our study), since it seems that these would be the greatest benefits of this therapy.
Darolutamide & time to treatment discontinuation in nmCRPC
