2) The expert faculty for this symposium was led by program chair @alantanmd Director of GU Medical Oncology @RushMedical, along with @AlanBryce9 of @MayoCancerCare @MayoClinic, & #MahaHussein MD of @NorthwesternMed. The program can be reviewed in 📽️at https://t.co/IzMFfDv9Av.
— @onc_ce (@onc_ce) July 26, 2023
4a) So let's start with the basics. #prostatecancer cells are androgen-dependent & androgen-deprivation therapy (#ADT) is the standard of care for #metastatic prostate cancer.
— @onc_ce (@onc_ce) July 26, 2023
5) Despite current #chemotherapies, including the utilization of novel androgen signaling inhibitors & immunotherapy, mortality is significantly increased. One strategy being evaluated in clinical trials is the use of #PARP inhibitors combined with #ADT. pic.twitter.com/kcjhRhWHtL
— @onc_ce (@onc_ce) July 26, 2023
6a) The primary #MOA of poly-ADP ribose polymerase inhibitors (#PARPi) is via induction of synthetic lethality in cells with underlying deficiencies in homologous recombination repair (#HRR). pic.twitter.com/IiCwyDIjVM
— @onc_ce (@onc_ce) July 26, 2023
6c) It's b, TMB increases dramatically as DNA double strand breaks accumulate. Keep going! pic.twitter.com/uL4dxVDJ08
— @onc_ce (@onc_ce) July 26, 2023
6e) Ongoing research is focused on identifying which #HRR alterations are best suited to predict response to #PARPi so that these therapies can be most effectively utilized in the clinic. Among other 🔥 topics, our faculty discussed this research at #AACR23. pic.twitter.com/ZJqVyziOrb
— @onc_ce (@onc_ce) July 26, 2023
8a) #PROfound pts had at least 1 #HRR alteration, & were eval'd in 2 cohorts: A (pts w/ #BRCA1, #BRCA2, or #ATM mutations) & B, (pts w/ alteration in any of 12 other prespecified genes (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, & RAD54L). pic.twitter.com/7RDN9PGSJF
— @onc_ce (@onc_ce) July 26, 2023
8c) Objective response rate (#ORR) was 33% in the #olaparib group and 2% in the control group. In the overall population of the study, the median rPFS also favored the olaparib group (5.8 months vs 3.5 months, HR 0.49, p<0.001). pic.twitter.com/7fmbR9xUWp
— @onc_ce (@onc_ce) July 26, 2023
8e) The adverse event profile of #olaparib was acceptable in #PROfound. pic.twitter.com/ln07hJO7ee
— @onc_ce (@onc_ce) July 26, 2023
9b) … tx'd w/ a starting dose of 600mg rucaparib BID ➡️ORR of 43.5% per independent rad review, 50.8% per investigator. #PSA response rate=54.8%, higher in pts with a #BRCA2 alteration.
— @onc_ce (@onc_ce) July 26, 2023
🔓https://t.co/mpZU6eTJhj pic.twitter.com/9vH6yQH3we
11a) #TRITON3 was a Ph 3 trial of #rucaparib vs chemotx or 2nd-line #ADT in pts w/#mCRPC + mutations in #BRCA or #ATM + disease progression following treatment w/ an #ARSI.https://t.co/Mls2iG58os pic.twitter.com/OH25QQftKs
— @onc_ce (@onc_ce) July 26, 2023
11c) At 62 mo, #rPFS was significantly longer in the #rucaparib group vs control group in both the BRCA subgroup (11.2 vs 6.4mos; HR 0.50) & in the #ITT (10.2 vs 6.4mos; HR 0.61). The most common reported #AEs in the #rucaparib group were fatigue & nausea. pic.twitter.com/iOsAOvpajY
— @onc_ce (@onc_ce) July 26, 2023
13) Summarizing where we were in early 2023: pic.twitter.com/dMkG5FFmxa
— @onc_ce (@onc_ce) July 26, 2023
15a) #ARSI first: Combo tx & the #PARPi #niraparib. In the Ph 3 #MAGNITUDE trial, niraparib + #abirateroneacetate + prednisone in 1L tx ➡️ significant ⬆️rPFS vs placebo + abiraterone.
— @onc_ce (@onc_ce) July 26, 2023
🔓 https://t.co/d4focYKL9O
Learn more in 📽️ at https://t.co/lPm4tKf8mR.
16a) #Talazoparib+ #enzalutamide:#Talazoparib is a #PARPi & also traps PARP on single-strand DNA breaks, preventing DNA repair & selectively killing tumor cells with #DDR alterations such as #BRCA1/2.
— @onc_ce (@onc_ce) July 26, 2023
See https://t.co/2yOTAVYfDM pic.twitter.com/EivM7zTkDD
16c) Ph 3 #TALAPRO_2 trial in ♂️ w/heavily pretreated, HRR-mutated #mCRPC ➡️#talazoparib + #enzalutamide superior to placebo plus enzalutamide for statistically significant & clinically meaningful improvement in #rPFS vs placebo + enzalutamide.https://t.co/D8CslrZRj7 pic.twitter.com/G7rS3e74n8
— @onc_ce (@onc_ce) July 26, 2023
16e) . . . and safety was acceptable: pic.twitter.com/XvPHRHCpbR
— @onc_ce (@onc_ce) July 26, 2023
17b) The primary endpoint is #rPFS, and secondary endpoints include overall survival, safety, and patient reported outcomes #PROs.https://t.co/WDS7MhnmGe
— @onc_ce (@onc_ce) July 26, 2023
19) Underway: pic.twitter.com/3enFFQzGmD
— @onc_ce (@onc_ce) July 26, 2023
20b) Median #rPFS for all pts = 16.1mo, 12-mo rPFS = 51.5%. In pts with #HRR alterations, median rPFS = 16.1mo. 53% of pts had a radiographic &/or PSA50 response. 4 of 17 pts had immune-related adverse events, but none was taken off trial for toxicity.
— @onc_ce (@onc_ce) July 26, 2023
21b) The authors concluded that nivolumab + rucaparib is active in pts with HRD+ chemotherapy-naïve #mCRPC, particularly among those w/#BRCA mutations. Longer follow-up is needed to better characterize the clinical benefits of adding nivolumab to rucaparib for this population.
— @onc_ce (@onc_ce) July 26, 2023
23a) #PARPi + #chemotherapy: it has been hoped that cytotoxic damage induced by chemo could facilitate synthetic lethality via PARPi. In a 25-patient single-arm study of pts w/#mCRPC, #veliparib + #temozolomide was studied.https://t.co/HlV2m0j2y0
— @onc_ce (@onc_ce) July 26, 2023
24a) #PARPi + #radiotherapy
— @onc_ce (@onc_ce) July 26, 2023
Radium-223 is a targeted alpha-particle tx used in #metastatic #prostatecancerw/symptomatic osseous disease, ➡️damage via DNA double-strand breaks.https://t.co/aRASipdxqJ
25) In the #COMRADE trial, radium-223 + #olaparib combo was investigated. Dose limiting toxicities included cytopenias, fatigue, and nausea. rPFS at 5 months was 58% (95% CI, 27%-80%).https://t.co/QdES9v1Oz3 pic.twitter.com/FZu0k4crJT
— @onc_ce (@onc_ce) July 26, 2023
27) In summary, existing data supports #PARPi as a #radiosensitizing agent
— @onc_ce (@onc_ce) July 26, 2023
👉 concern for overlapping toxicities with #myelosuppression
👉PARPi most likely needs to be dose reduced in this setting
👉 it is unclear if the case is compelling enough to support further development
29a) And one quick question . . . did you pay attention? Which is thought to be the most potent #PARPi?
— @onc_ce (@onc_ce) July 26, 2023
30) All in all . . . pic.twitter.com/k8CcpAbV4R
— @onc_ce (@onc_ce) July 26, 2023
31) So FOLLOW @onc_ce and watch this space for more readily-accessed education from experts like @alantanmd, @AlanBryce9, & #MahaHussein. For now, grab 0.75hr 🆓 CE/#CME at https://t.co/ZaDRkKS5ZH, & earn ANOTHER hour from this esteemed faculty by 📽️at https://t.co/IzMFfDv9Av.
— @onc_ce (@onc_ce) July 26, 2023