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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.
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
RAD54L F82S Olaparib
ATM S1993Rfs*23 Olaparib
ATM T2333fs Olaparib
ATM W2104* Olaparib
RAD51C R366Q Olaparib
CHEK2 N166S Olaparib
RAD51C K131I Olaparib
ATM L2890V Olaparib
CHEK2 S357F Olaparib
CHEK2 A247D Olaparib
ATM K293* Olaparib
CHEK2 E321* Olaparib
CHEK2 E107_K197del Olaparib
ATM R2849P Olaparib
CHEK2 H371Y Olaparib
CHEK2 T476M Olaparib
CHEK2 T367Mfs*15 Olaparib
ATM H1380Y Olaparib
CHEK2 R148G Olaparib
ATM R2034P Olaparib
RAD51C R312W Olaparib
ATM S2855_V2856delinsRI Olaparib
RAD51D V203E Olaparib
ATM E1072* Olaparib
ATM A2067D Olaparib
CHEK2 K135Nfs*26 Olaparib
CHEK2 R145W Olaparib
CHEK2 G306A Olaparib
ATM N81Tfs*20 Olaparib
CHEK2 P85R Olaparib
ATM F2571Yfs*4 Olaparib
CHEK2 I160R Olaparib
CHEK2 R474H Olaparib
CHEK2 C284Y Olaparib
ATM S1455R Olaparib
CHEK2 E122Dfs*8 Olaparib
ATM T2666A Olaparib
ATM N765Kfs*12 Olaparib
RAD51C C135Y Olaparib
CHEK2 P85L Olaparib
CHEK2 H143R Olaparib
CHEK2 S140N Olaparib
RAD51C G162Efs*9 Olaparib
CHEK2 I160T Olaparib
CHEK2 D347N Olaparib
ATM E2039K Olaparib
RAD51C L226P Olaparib
ATM E1978* Olaparib
RAD51C R193* Olaparib
ATM I1581Nfs*5 Olaparib
CHEK2 M304T Olaparib
ATM P292L Olaparib
RAD54L K189A Olaparib
CHEK2 R474C Olaparib
ATM W57* Olaparib
ATM V2288fs Olaparib
ATM G2718_K2756del Olaparib
ATM S1993fs Olaparib
ATM I1453fs Olaparib
CHEK2 T387S Olaparib
CHEK2 S372F Olaparib
CHEK2 F202fs Olaparib
RAD51B R8* Olaparib
ATM R2849* Olaparib
CHEK2 G14Afs*47 Olaparib
CHEK2 K373E Olaparib
ATM R2506_N2543del Olaparib
ATM Q1171Tfs*8 Olaparib
RAD51C A279P Olaparib
ATM H2554D Olaparib
ATM R1875* Olaparib
CHEK2 T410fs Olaparib
ATM W524* Olaparib
ATM G2867R Olaparib
CHEK2 P426R Olaparib
ATM S421* Olaparib
ATM R2138Kfs*8 Olaparib
CHEK2 I160M Olaparib
ATM V1268fs Olaparib
ATM L2427P Olaparib
RAD54L loss Olaparib
CHEK2 T366fs Olaparib
CHEK1 R379* Olaparib
CHEK2 W485G Olaparib
ATM Q2277* Olaparib
ATM L1874F Olaparib
ATM S2394L Olaparib
ATM F2732V Olaparib
ATM E2304Gfs*69 Olaparib
CHEK2 R117G Olaparib
ATM S1403fs Olaparib
ATM E390* Olaparib
ATM E343* Olaparib
RAD51C F103V Olaparib
ATM Y1442* Olaparib
ATM S131* Olaparib
RAD51C E80* Olaparib
CHEK2 F292fs Olaparib
RAD54L P85A Olaparib
RAD51D del Olaparib
ATM R1466* Olaparib
CHEK2 N185fs Olaparib
ATM E522* Olaparib
ATM D1682Y Olaparib
ATM V278fs Olaparib
ATM E518fs Olaparib
ATM L2953Tfs*3 Olaparib
RAD51C V140G Olaparib
ATM W2109* Olaparib
ATM Q2522fs Olaparib
ATM R1618* Olaparib
RAD51C A155E Olaparib
RAD51D G112A Olaparib
CHEK2 V198Ffs*7 Olaparib
CHEK2 E239K Olaparib
RAD51C loss Olaparib
ATM E2272* Olaparib
CHEK2 F125S Olaparib
CHEK2 D82_E86del Olaparib
CHEK2 E394K Olaparib
CHEK2 R181C Olaparib
RAD51D S207L Olaparib
CHEK2 Q209* Olaparib
RAD51D K91fs Olaparib
ATM A1742P Olaparib
ATM K468fs Olaparib
CHEK2 F475Lfs*7 Olaparib
ATM L1956H Olaparib
ATM V2119fs Olaparib
CHEK2 Y139* Olaparib
CHEK2 R95* Olaparib
RAD51C L27P Olaparib
ATM T2902fs Olaparib
ATM Y2371* Olaparib
ATM Q2730P Olaparib
RAD51C S163R Olaparib
ATM P2699S Olaparib
ATM P604S Olaparib
CHEK2 D347A Olaparib
RAD54L S49E Olaparib
ATM L2738* Olaparib
CHEK2 C420T Olaparib
ATM M1484Rfs*15 Olaparib
ATM Q1970* Olaparib
CHEK2 C108R Olaparib
ATM S2812Vfs*3 Olaparib
RAD51C V140E Olaparib
CHEK2 F169Lfs*2 Olaparib
ATM R250Sfs*3 Olaparib
CHEK2 E161del Olaparib
CHEK2 I157T Olaparib
CHEK1 inact mut Olaparib
ATM R2034* Olaparib
ATM R1898* Olaparib
RAD51B Y46* Olaparib
CHEK2 A392V Olaparib
ATM C540* Olaparib
RAD51D inact mut Olaparib
ATM E1666* Olaparib
CHEK2 H54Pfs*6 Olaparib
ATM Q2972* Olaparib
CHEK2 S422Vfs*15 Olaparib
ATM E2039* Olaparib
RAD54L L381Cfs*8 Olaparib
CHEK2 I189V Olaparib
ATM V566Ifs*6 Olaparib
ATM I1849fs Olaparib
RAD51C E146* Olaparib
CHEK2 T59K Olaparib
CHEK2 K244R Olaparib
RAD51C R237P Olaparib
RAD51B loss Olaparib
CHEK2 K224E Olaparib
ATM K1807E Olaparib
CHEK2 L326P Olaparib
CHEK2 L216* Olaparib
CHEK2 Q34Vfs*42 Olaparib
ATM T2333Nfs*40 Olaparib
RAD54L inact mut Olaparib
CHEK2 Q10fs Olaparib
RAD51C G302V Olaparib
ATM H2038Y Olaparib
ATM E277* Olaparib
ATM N2326_K2363del Olaparib
CHEK2 L309P Olaparib
ATM K2756* Olaparib
ATM V2424G Olaparib
RAD51D G107V Olaparib
RAD51C S105* Olaparib
ATM F2827C Olaparib
RAD51C del Olaparib
ATM P960H Olaparib
ATM Q2800* Olaparib
ATM R1730* Olaparib
ATM V2716A Olaparib
CHEK2 E351K Olaparib
ATM L2338P Olaparib
CHEK2 G306E Olaparib
RAD51C L265* Olaparib
ATM G2765S Olaparib
RAD51C inact mut Olaparib
RAD54L E436* Olaparib
ATM R2832C Olaparib
CHEK2 G370E Olaparib
ATM loss Olaparib
RAD51D loss Olaparib
ATM S1905Ifs*25 Olaparib
ATM L2452P Olaparib
CHEK2 K253* Olaparib
CHEK2 K287fs Olaparib
RAD51B del Olaparib
CHEK2 K249R Olaparib
ATM F1025L Olaparib
ATM Y54* Olaparib
CHEK2 G229S Olaparib
ATM Q2297* Olaparib
ATM W412* Olaparib
ATM R3008C Olaparib
CHEK2 R180H Olaparib
ATM N1650S Olaparib
CHEK2 R474L Olaparib
ATM V519I Olaparib
ATM S824F Olaparib
RAD51C Q133K Olaparib
ATM Q628Pfs*7 Olaparib
ATM R3047* Olaparib
ATM Y1961C Olaparib
CHEK2 R318H Olaparib
ATM I1294Nfs*8 Olaparib
ATM Q1906* Olaparib
RAD51C D348V Olaparib
CHEK2 Q27* Olaparib
ATM C353fs Olaparib
ATM R2993* Olaparib
ATM A2062V Olaparib
CHEK2 E87* Olaparib
CHEK1 del Olaparib
RAD51C D159Y Olaparib
CHEK2 H143Y Olaparib
CHEK2 D409N Olaparib
RAD51C T287A Olaparib
ATM L762Qfs*4 Olaparib
ATM Q1636Rfs*10 Olaparib
CHEK2 S428F Olaparib
CHEK2 D162G Olaparib
RAD51D Q41* Olaparib
CHEK2 G414E Olaparib
ATM S2407* Olaparib
ATM L2572fs Olaparib
ATM I2701Nfs*17 Olaparib
CHEK2 A230P Olaparib
CHEK2 Y390S Olaparib
CHEK2 E275* Olaparib
ATM E668* Olaparib
CHEK2 D293fs Olaparib
CHEK2 L183F Olaparib
RAD51C G125V Olaparib
ATM T1743I Olaparib
CHEK2 S372Y Olaparib
ATM E2187* Olaparib
CHEK2 H483R Olaparib
ATM R250* Olaparib
RAD54L del Olaparib
RAD51C G264S Olaparib
RAD51C G114V Olaparib
ATM T1200Lfs*7 Olaparib
RAD51D G96C Olaparib
CHEK2 L236P Olaparib
RAD51C R214C Olaparib
ATM L1465P Olaparib
ATM T2947S Olaparib
CHEK2 S412R Olaparib
RAD51C G130A Olaparib
ATM R3008H Olaparib
RAD51D V200* Olaparib
ATM R2912Efs*26 Olaparib
RAD51C Q133E Olaparib
RAD51C T132P Olaparib
CHEK2 E64K Olaparib
ATM S751* Olaparib
CHEK2 T476K Olaparib
ATM S1135_K1192del Olaparib
ATM C2488Y Olaparib
ATM I2629fs Olaparib
ATM E2977Rfs*2 Olaparib
ATM K468Efs*18 Olaparib
CHEK2 C385R Olaparib
CHEK2 E321K Olaparib
CHEK2 A392P Olaparib
CHEK2 del Olaparib
ATM Q2397* Olaparib
ATM G2083* Olaparib
RAD51C V156D Olaparib
RAD51C D159A Olaparib
ATM I10fs Olaparib
ATM P1069fs Olaparib
ATM A2602fs Olaparib
RAD54L E297* Olaparib
CHEK2 L183S Olaparib
CHEK2 Y424H Olaparib
ATM S719* Olaparib
ATM D1682H Olaparib
ATM S2017fs Olaparib
ATM dec exp Olaparib
ATM Y1229* Olaparib
CHEK2 A392S Olaparib
ATM A59S Olaparib
CHEK2 R406Vfs*8 Olaparib
RAD51D D206A Olaparib
ATM Q1579fs Olaparib
CHEK2 T367fs Olaparib
ATM R805* Olaparib
CHEK2 F169L Olaparib
RAD51C G150E Olaparib
RAD51C D108G Olaparib
RAD51B L103* Olaparib
CHEK2 R117A Olaparib
CHEK2 L174V Olaparib
RAD54L Q90* Olaparib
CHEK2 N352D Olaparib
ATM S333F Olaparib
ATM I1441fs Olaparib
ATM S978fs Olaparib
ATM P2974L Olaparib
ATM R2691C Olaparib
ATM S214fs Olaparib
CHEK2 Y390C Olaparib
ATM V1538fs Olaparib
ATM N3033* Olaparib
ATM Q284* Olaparib
ATM S1455Vfs*3 Olaparib
RAD51C T132R Olaparib
ATM A302fs Olaparib
ATM inact mut Olaparib
CHEK2 G167R Olaparib
RAD51B inact mut Olaparib
RAD51C G153D Olaparib
ATM W1058* Olaparib
ATM R2547_S2549del Olaparib
RAD51C L138F Olaparib
ATM R1882* Olaparib
ATM L1449* Olaparib
RAD51C L219S Olaparib
CHEK2 E273K Olaparib
RAD54L Y309* Olaparib
ATM negative Olaparib
ATM R2598* Olaparib
CHEK2 R382* Olaparib
RAD51C C135R Olaparib
ATM S2592C Olaparib
CHEK2 G386R Olaparib
RAD51C T102I Olaparib
ATM Y2019C Olaparib
ATM D2708N Olaparib
ATM R337S Olaparib
ATM P2699L Olaparib
ATM I1681V Olaparib
CHEK2 T323P Olaparib
RAD51C T121R Olaparib
CHEK2 inact mut Olaparib
CHEK2 loss Olaparib
RAD54L K189R Olaparib
ATM V1268* Olaparib
CHEK2 W93Gfs*17 Olaparib
RAD51C R258H Olaparib
ATM L2427_R2428del Olaparib
CHEK2 D438Y Olaparib
CHEK2 W93R Olaparib
RAD51C Q143R Olaparib
RAD51D E37* Olaparib
RAD54L R75* Olaparib
CHEK2 D265_H282del Olaparib
ATM del Olaparib
CHEK2 A237T Olaparib
ATM K1410* Olaparib
ATM K2811fs Olaparib
CHEK2 M381* Olaparib
CHEK2 E149Ifs*6 Olaparib
CHEK2 N290Ifs*15 Olaparib
ATM K2749I Olaparib
ATM L804fs Olaparib
ATM V1941L 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
RAD54L inact mut prostate cancer sensitive Olaparib FDA approved - On Companion Diagnostic Actionable In a Phase III trial (PROfound) that supported FDA approval, Lynparza (olaparib) improved median imaging-based progression-free survival (5.8 vs 3.5 mo, HR 0.49, p<0.001) compared to control in metastatic castration-resistant prostate cancer patients harboring deleterious or suspected deleterious mutations in homologous recombination repair genes who progressed on hormone therapy, HR for progression or death was 0.33 in RAD54L-mutant patients (PMID: 32343890; NCT02987543). detail... detail... 32343890
CHEK2 inact mut prostate cancer sensitive Olaparib FDA approved - On Companion Diagnostic Actionable In a Phase III trial (PROfound) that supported FDA approval, Lynparza (olaparib) improved median imaging-based progression-free survival (5.8 vs 3.5 mo, HR 0.49, p<0.001) compared to control in metastatic castration-resistant prostate cancer patients harboring deleterious or suspected deleterious mutations in homologous recombination repair genes who progressed on hormone therapy, HR for progression or death was 0.87 in CHEK2-mutant patients (PMID: 32343890; NCT02987543). detail... detail... 32343890
RAD51D 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 significantly improved median imaging-based progression-free survival (5.8 vs 3.5 mo, HR 0.49, p<0.001) compared to control in patients with metastatic castration-resistant prostate cancer who progressed on hormone therapy and harbored deleterious or suspected deleterious mutations in homologous recombination repair genes, including RAD51D (PMID: 32343890; NCT02987543). detail... detail... 32343890
RAD51B 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 significantly improved median imaging-based progression-free survival (5.8 vs 3.5 mo, HR 0.49, p<0.001) compared to control in patients with metastatic castration-resistant prostate cancer who progressed on hormone therapy and harbored deleterious or suspected deleterious mutations in homologous recombination repair genes, including RAD51B (PMID: 32343890; NCT02987543). detail... detail... 32343890
RAD51C 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 significantly improved median imaging-based progression-free survival (5.8 vs 3.5 mo, HR 0.49, p<0.001) compared to control in patients with metastatic castration-resistant prostate cancer who progressed on hormone therapy and harbored deleterious or suspected deleterious mutations in homologous recombination repair genes, including RAD51C (PMID: 32343890; NCT02987543). detail... detail... 32343890
CHEK1 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 significantly improved median imaging-based progression-free survival (5.8 vs 3.5 mo, HR 0.49, p<0.001) compared to control in patients with metastatic castration-resistant prostate cancer who progressed on hormone therapy and harbored deleterious or suspected deleterious mutations in homologous recombination repair genes, including CHEK1 (PMID: 32343890; NCT02987543). detail... detail... 32343890
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) improved progression-free survival (7.4 vs 3.6 mo, HR 0.34, p<0.001), objective response rate (33% vs 2%, OR 20.86, p<0.001), and median overall survival (18.5 vs 15.1 mo, HR 0.64, p=0.02) compared to control in metastatic castration-resistant prostate cancer patients harboring deleterious or suspected deleterious BRCA or ATM mutations, HR for progression or death was 1.04 in ATM-mutant patients (PMID: 32343890; NCT02987543). detail... 32343890 detail...