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Ref Type Journal Article
PMID (32343890)
Authors de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M
Title Olaparib for Metastatic Castration-Resistant Prostate Cancer.
Journal The New England journal of medicine
Vol
Issue
Date 2020 Apr 28
URL
Abstract Text Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in patients with prostate and other cancers.We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men 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. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician's choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review.In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib.In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone. (Funded by AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).

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Molecular Profile Treatment Approach
ATM S214fs Olaparib
ATM R250* Olaparib
ATM K468fs Olaparib
ATM Q2972* Olaparib
ATM H1380Y Olaparib
ATM S131* Olaparib
ATM E518fs Olaparib
ATM S2394L Olaparib
ATM L2427P Olaparib
ATM H2038Y Olaparib
ATM N2326_K2363del Olaparib
ATM C540* Olaparib
ATM S2407* Olaparib
ATM V2424G Olaparib
ATM del Olaparib
ATM V1268fs Olaparib
ATM R250Sfs*3 Olaparib
ATM L2427_R2428del Olaparib
ATM K2756* Olaparib
ATM E1978* Olaparib
ATM R805* Olaparib
ATM R3047* Olaparib
ATM L2953Tfs*3 Olaparib
ATM E343* Olaparib
ATM loss Olaparib
ATM F2571Yfs*4 Olaparib
ATM A302fs Olaparib
ATM S421* Olaparib
ATM E2977Rfs*2 Olaparib
ATM I1681V Olaparib
ATM R1730* Olaparib
ATM R1466* Olaparib
ATM R2691C Olaparib
ATM T2902fs Olaparib
ATM S1905Ifs*25 Olaparib
ATM W412* Olaparib
ATM L2338P Olaparib
ATM D2708N Olaparib
ATM R2034P Olaparib
ATM T2947S Olaparib
ATM S824F Olaparib
ATM V566Ifs*6 Olaparib
ATM E2272* Olaparib
ATM I10fs Olaparib
ATM L1874F Olaparib
ATM E1666* Olaparib
ATM V519I Olaparib
ATM V2716A Olaparib
ATM K1807E Olaparib
ATM V1268* Olaparib
ATM G2083* Olaparib
ATM E390* Olaparib
ATM Q1906* Olaparib
ATM Q1171Tfs*8 Olaparib
ATM Y2019C Olaparib
ATM E2304Gfs*69 Olaparib
ATM E522* Olaparib
ATM V278fs Olaparib
ATM Q2730P Olaparib
ATM R2138Kfs*8 Olaparib
ATM S2812Vfs*3 Olaparib
ATM R2598* Olaparib
ATM I2701Nfs*17 Olaparib
ATM R3008H Olaparib
ATM E1072* Olaparib
ATM R2993* Olaparib
ATM V1941L Olaparib
ATM K1410* Olaparib
ATM F2732V Olaparib
ATM L2890V Olaparib
ATM N765Kfs*12 Olaparib
ATM E2039* Olaparib
ATM V1538fs Olaparib
ATM I1849fs Olaparib
ATM C353fs Olaparib
ATM S1403fs Olaparib
ATM Y1961C Olaparib
ATM P2974L Olaparib
ATM L1956H Olaparib
ATM Q2800* Olaparib
ATM L804fs Olaparib
ATM P1069fs Olaparib
ATM W57* Olaparib
ATM T2333fs Olaparib
ATM A2067D Olaparib
ATM R1882* Olaparib
ATM G2867R Olaparib
ATM R2849P Olaparib
ATM Y54* Olaparib
ATM Y2371* Olaparib
ATM S978fs Olaparib
ATM K293* Olaparib
ATM Q2397* Olaparib
ATM I2629fs Olaparib
ATM F2827C Olaparib
ATM Q628Pfs*7 Olaparib
ATM E2187* Olaparib
ATM Q1579fs Olaparib
ATM D1682Y Olaparib
ATM negative Olaparib
ATM S2855_V2856delinsRI Olaparib
ATM W2109* Olaparib
ATM Q2277* Olaparib
ATM G2718_K2756del Olaparib
ATM K2749I Olaparib
ATM V2662del Olaparib
ATM P292L Olaparib
ATM A2602fs Olaparib
ATM C2488Y Olaparib
ATM N3033* Olaparib
ATM S2017fs Olaparib
ATM R2547_S2549del Olaparib
ATM D1682H Olaparib
ATM R3008C Olaparib
ATM P604S Olaparib
ATM T2666A Olaparib
ATM S719* Olaparib
ATM W2104* Olaparib
ATM I1294Nfs*8 Olaparib
ATM I1581Nfs*5 Olaparib
ATM F1025L Olaparib
ATM Q2297* Olaparib
ATM G2765S Olaparib
ATM S1455R Olaparib
ATM R337S Olaparib
ATM P960H Olaparib
ATM L2452P Olaparib
ATM inact mut Olaparib
ATM K468Efs*18 Olaparib
ATM A2062V Olaparib
ATM S2592C Olaparib
ATM T1200Lfs*7 Olaparib
ATM S1455Vfs*3 Olaparib
ATM E2039K Olaparib
ATM R2849* Olaparib
ATM R1618* Olaparib
ATM R2506_N2543del Olaparib
ATM V2119fs Olaparib
ATM T2333Nfs*40 Olaparib
ATM A1742P Olaparib
ATM T1743I Olaparib
ATM L1465P Olaparib
ATM H2554D Olaparib
ATM R2034* Olaparib
ATM L1449* Olaparib
ATM Q1636Rfs*10 Olaparib
ATM P2699L Olaparib
ATM K2811fs Olaparib
ATM A59S Olaparib
ATM R2832C Olaparib
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ATM inact mut prostate cancer sensitive Olaparib FDA approved - On Companion Diagnostic Actionable In a Phase III trial (PROfound) that supported FDA approval, Lynparza (olaparib) treatment improved progression-free survival (7.4 vs 3.6 mo, HR=0.34, p<0.001), objective response rate (33%, 28/84 vs 2%, 1/43, OR=20.86, p<0.001), and median time to pain progression (HR=0.44, p=0.02) compared to control in patients with metastatic castration-resistant prostate cancer harboring deleterious or suspected deleterious mutations in BRCA1/2 or ATM who progressed on hormone therapy (PMID: 32343890; NCT02987543). detail... 32343890 detail...