Editing Castrate-Resistant Prostate Cancer (section)

====== Olaparib ======
* Homologous recombination repair (HRR) gene mutations occur in approximately 20–30% of prostate cancers from patients with metastatic disease, with the most common altered gene being BRCA2.
** Defective HRR renders a cancer susceptible to poly (ADP-ribose) polymerase (PARP) inhibition in a form of synthetic lethality.
* '''MOA: poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor'''
* '''Indications'''
** '''2021 CUA CPRC Guidelines'''
*** '''mCPRC and homologous recombination repair (HRR) mutation who have progressed on a previous androgen receptor-axis-targeted therapy (ARAT) i.e., abiraterone, enzalutamide, apalutamide, darolutamide'''
** Health Canada approval for patients with deleterious or suspected deleterious germline or somatic BRCA1/2 or ATM mutations who have progressed following prior treatment with an NHT (i.e., abiraterone, enzalutamide, apalutamide, darolutamide).
** U.S. Food and Drug Administration approved prostate cancers harboring a broader spectrum of 11 additional genes that are directly or indirectly involved in HRR (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L), which comprised an additional cohort in the PROfound study.
** European regulatory authority approved only for BRCA1/2 alterations.
* '''PROfound'''
** Population: 387 patients with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). 
*** All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. 
**** Cohort A (245 patients) had at least one alteration in ''BRCA1'', ''BRCA2'', or ''ATM''
**** Cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue.
** Randomized to in a 2:1 ratio to receive olaparib or the physician’s choice of enzalutamide or abiraterone (control)
** Primary outcome: imaging-based progression-free survival in cohort A
** Results:
*** Imaging-based progression-free survival in cohort A: significantly improved in the olaparib group (7.4 months olaparib vs. vs. 3.6 months control; hazard ratio for progression or death, 0.34)
*** Overall survival improved with olaparib by 4.4 months in cohort A (19.1 months olaparib vs. 15.7 months control) and by 2.6 months in cohort B
*** Adverse events: anemia, fatigue or asthenia, nausea, diarrhea
** de Bono, Johann, et al."Olaparib for metastatic castration-resistant prostate cancer." ''New England Journal of Medicine'' 382.22 (2020): 2091-2102.
** Hussain, Maha, et al. "Survival with olaparib in metastatic castration-resistant prostate cancer." ''New England Journal of Medicine'' 383.24 (2020): 2345-2357.