Background Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has previously shown efficacy in a phase 2 study when given in capsule formulation to all-comer patients with platinum-sensitive, relapsed high-grade serous ovarian cancer. We aimed to confirm these findings in patients with a BRCA1 or BRCA2 (BRCA1/2) mutation using a tablet formulation of olaparib. Methods This international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial evaluated olaparib tablet maintenance treatment in platinum-sensitive, relapsed ovarian cancer patients with a BRCA1/2 mutation who had received at least two lines of previous chemotherapy. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status at baseline of 0–1 and histologically confirmed, relapsed, high-grade serous ovarian cancer or high-grade endometrioid cancer, including primary peritoneal or fallopian tube cancer. Patients were randomly assigned 2:1 to olaparib (300 mg in two 150 mg tablets, twice daily) or matching placebo tablets using an interactive voice and web response system. Randomisation was stratified by response to previous platinum chemotherapy (complete vs partial) and length of platinum-free interval (6–12 months vs ≥12 months) and treatment assignment was masked for patients, those giving the interventions, data collectors, and data analysers. The primary endpoint was investigator-assessed progression-free survival and we report the primary analysis from this ongoing study. The efficacy analyses were done on the intention-to-treat population; safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01874353, and is ongoing and no longer recruiting patients. Findings Between Sept 3, 2013, and Nov 21, 2014, we enrolled 295 eligible patients who were randomly assigned to receive olaparib (n=196) or placebo (n=99). One patient in the olaparib group was randomised in error and did not receive study treatment. Investigator-assessed median progression-free survival was significantly longer with olaparib (19·1 months [95% CI 16·3–25·7]) than with placebo (5·5 months [5·2–5·8]; hazard ratio [HR] 0·30 [95% CI 0·22–0·41], p<0·0001). The most common adverse events of grade 3 or worse severity were anaemia (38 [19%] of 195 patients in the olaparib group vs two [2%] of 99 patients in the placebo group), fatigue or asthenia (eight [4%] vs two [2%]), and neutropenia (ten [5%] vs four [4%]). Serious adverse events were experienced by 35 (18%) patients in the olaparib group and eight (8%) patients in the placebo group. The most common in the olaparib group were anaemia (seven [4%] patients), abdominal pain (three [2%] patients), and intestinal obstruction (three [2%] patients). The most common in the placebo group were constipation (two [2%] patients) and intestinal obstruction (two [2%] patients). One (1%) patient in the olaparib group had a treatment-related adverse event (acute myeloid leukaemia) with an outcome of death. Interpretation Olaparib tablet maintenance treatment provided a significant progression-free survival improvement with no detrimental effect on quality of life in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Apart from anaemia, toxicities with olaparib were low grade and manageable. Funding AstraZeneca.

Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21). a double-blind, randomised, placebo-controlled, phase 3 trial / Pujade-Lauraine, E.; Ledermann, J. A.; Selle, F.; Gebski, V.; Penson, R. T.; Oza, A. M.; Korach, J.; Huzarski, T.; Poveda, A.; Pignata, S.; Friedlander, M.; Colombo, N.; Harter, P.; Fujiwara, K.; Ray-Coquard, I.; Banerjee, S.; Liu, J.; Lowe, E. S.; Bloomfield, R.; Pautier, P.; Korach, J.; Huzarski, T.; Byrski, T.; Pautier, P.; Harter, P.; Colombo, N.; Scambia, G.; Nicoletto, M.; Nussey, F.; Clamp, A.; Penson, R.; Oza, A.; Poveda Velasco, A.; Rodrigues, M.; Lotz, J. -P.; Selle, F.; Ray-Coquard, I.; Provencher, D.; Prat Aparicio, A.; Vidal Boixader, L.; Scott, STEPHEN PETER CARLO; Tamura, K.; Yunokawa, M.; Lisyanskaya, A.; Medioni, J.; Pecuchet, N.; Dubot, C.; de la Motte Rouge, T.; Kaminsky, M. -C.; Weber, B.; Lortholary, A.; Parkinson, C.; Ledermann, J.; Williams, CAROLYN S.; Banerjee, S.; Cosin, J.; Hoffman, J.; Penson, R.; Plante, M.; Covens, A.; Sonke, G.; Joly, F.; Floquet, A.; Banerjee, S.; Hirte, H.; Amit, A.; Park-Simon, T. -W.; Matsumoto, K.; Tjulandin, S.; Kim, J. H.; Gladieff, L.; Sabbatini, R.; O'Malley, D.; Timmins, P.; Kredentser, D.; Lainez Milagro, N.; Barretina Ginesta, M. P.; Tibau Martorell, A.; Gomez de Liano Lista, A.; Ojeda Gonzalez, B.; Mileshkin, L.; Mandai, M.; Boere, I.; Ottevanger, P.; Nam, J. -H.; Filho, E.; Hamizi, S.; Cognetti, F.; Warshal, D.; Dickson-Michelson, E.; Kamelle, S.; Mckenzie, N.; RODRIGUEZ CASTILLO, GUILLERMO ANDRES; Armstrong, D.; Chalas, E.; Celano, P.; Behbakht, K.; Davidson, S.; Welch, S.; Helpman, L.; Fishman, A.; Bruchim, I.; Sikorska, M.; Slowinska, A.; Rogowski, W.; Bidzinski, M.; Spiewankiewicz, B.; Casado Herraez, A.; Mendiola Fernandez, C.; Gropp-Meier, M.; Saito, T.; Takehara, K.; Enomoto, T.; Watari, H.; Choi, C. H.; Kim, B. -G.; Kim, J. W.; Hegg, R.; Vergote, I.. - In: THE LANCET ONCOLOGY. - ISSN 1470-2045. - 18:9(2017), pp. 1274-1284. [10.1016/S1470-2045(17)30469-2]

Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21). a double-blind, randomised, placebo-controlled, phase 3 trial

Liu J.;SCOTT, STEPHEN PETER CARLO;WILLIAMS, CAROLYN S.;Cognetti F.;RODRIGUEZ CASTILLO, GUILLERMO ANDRES;
2017

Abstract

Background Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has previously shown efficacy in a phase 2 study when given in capsule formulation to all-comer patients with platinum-sensitive, relapsed high-grade serous ovarian cancer. We aimed to confirm these findings in patients with a BRCA1 or BRCA2 (BRCA1/2) mutation using a tablet formulation of olaparib. Methods This international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial evaluated olaparib tablet maintenance treatment in platinum-sensitive, relapsed ovarian cancer patients with a BRCA1/2 mutation who had received at least two lines of previous chemotherapy. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status at baseline of 0–1 and histologically confirmed, relapsed, high-grade serous ovarian cancer or high-grade endometrioid cancer, including primary peritoneal or fallopian tube cancer. Patients were randomly assigned 2:1 to olaparib (300 mg in two 150 mg tablets, twice daily) or matching placebo tablets using an interactive voice and web response system. Randomisation was stratified by response to previous platinum chemotherapy (complete vs partial) and length of platinum-free interval (6–12 months vs ≥12 months) and treatment assignment was masked for patients, those giving the interventions, data collectors, and data analysers. The primary endpoint was investigator-assessed progression-free survival and we report the primary analysis from this ongoing study. The efficacy analyses were done on the intention-to-treat population; safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01874353, and is ongoing and no longer recruiting patients. Findings Between Sept 3, 2013, and Nov 21, 2014, we enrolled 295 eligible patients who were randomly assigned to receive olaparib (n=196) or placebo (n=99). One patient in the olaparib group was randomised in error and did not receive study treatment. Investigator-assessed median progression-free survival was significantly longer with olaparib (19·1 months [95% CI 16·3–25·7]) than with placebo (5·5 months [5·2–5·8]; hazard ratio [HR] 0·30 [95% CI 0·22–0·41], p<0·0001). The most common adverse events of grade 3 or worse severity were anaemia (38 [19%] of 195 patients in the olaparib group vs two [2%] of 99 patients in the placebo group), fatigue or asthenia (eight [4%] vs two [2%]), and neutropenia (ten [5%] vs four [4%]). Serious adverse events were experienced by 35 (18%) patients in the olaparib group and eight (8%) patients in the placebo group. The most common in the olaparib group were anaemia (seven [4%] patients), abdominal pain (three [2%] patients), and intestinal obstruction (three [2%] patients). The most common in the placebo group were constipation (two [2%] patients) and intestinal obstruction (two [2%] patients). One (1%) patient in the olaparib group had a treatment-related adverse event (acute myeloid leukaemia) with an outcome of death. Interpretation Olaparib tablet maintenance treatment provided a significant progression-free survival improvement with no detrimental effect on quality of life in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Apart from anaemia, toxicities with olaparib were low grade and manageable. Funding AstraZeneca.
2017
olaparib tablets; brca1/2 mutation; phase 3 trial
01 Pubblicazione su rivista::01a Articolo in rivista
Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21). a double-blind, randomised, placebo-controlled, phase 3 trial / Pujade-Lauraine, E.; Ledermann, J. A.; Selle, F.; Gebski, V.; Penson, R. T.; Oza, A. M.; Korach, J.; Huzarski, T.; Poveda, A.; Pignata, S.; Friedlander, M.; Colombo, N.; Harter, P.; Fujiwara, K.; Ray-Coquard, I.; Banerjee, S.; Liu, J.; Lowe, E. S.; Bloomfield, R.; Pautier, P.; Korach, J.; Huzarski, T.; Byrski, T.; Pautier, P.; Harter, P.; Colombo, N.; Scambia, G.; Nicoletto, M.; Nussey, F.; Clamp, A.; Penson, R.; Oza, A.; Poveda Velasco, A.; Rodrigues, M.; Lotz, J. -P.; Selle, F.; Ray-Coquard, I.; Provencher, D.; Prat Aparicio, A.; Vidal Boixader, L.; Scott, STEPHEN PETER CARLO; Tamura, K.; Yunokawa, M.; Lisyanskaya, A.; Medioni, J.; Pecuchet, N.; Dubot, C.; de la Motte Rouge, T.; Kaminsky, M. -C.; Weber, B.; Lortholary, A.; Parkinson, C.; Ledermann, J.; Williams, CAROLYN S.; Banerjee, S.; Cosin, J.; Hoffman, J.; Penson, R.; Plante, M.; Covens, A.; Sonke, G.; Joly, F.; Floquet, A.; Banerjee, S.; Hirte, H.; Amit, A.; Park-Simon, T. -W.; Matsumoto, K.; Tjulandin, S.; Kim, J. H.; Gladieff, L.; Sabbatini, R.; O'Malley, D.; Timmins, P.; Kredentser, D.; Lainez Milagro, N.; Barretina Ginesta, M. P.; Tibau Martorell, A.; Gomez de Liano Lista, A.; Ojeda Gonzalez, B.; Mileshkin, L.; Mandai, M.; Boere, I.; Ottevanger, P.; Nam, J. -H.; Filho, E.; Hamizi, S.; Cognetti, F.; Warshal, D.; Dickson-Michelson, E.; Kamelle, S.; Mckenzie, N.; RODRIGUEZ CASTILLO, GUILLERMO ANDRES; Armstrong, D.; Chalas, E.; Celano, P.; Behbakht, K.; Davidson, S.; Welch, S.; Helpman, L.; Fishman, A.; Bruchim, I.; Sikorska, M.; Slowinska, A.; Rogowski, W.; Bidzinski, M.; Spiewankiewicz, B.; Casado Herraez, A.; Mendiola Fernandez, C.; Gropp-Meier, M.; Saito, T.; Takehara, K.; Enomoto, T.; Watari, H.; Choi, C. H.; Kim, B. -G.; Kim, J. W.; Hegg, R.; Vergote, I.. - In: THE LANCET ONCOLOGY. - ISSN 1470-2045. - 18:9(2017), pp. 1274-1284. [10.1016/S1470-2045(17)30469-2]
File allegati a questo prodotto
File Dimensione Formato  
Pujade-Lauraine_Olaparib-tablets_2017.pdf

solo gestori archivio

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 418.55 kB
Formato Adobe PDF
418.55 kB Adobe PDF   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1309646
Citazioni
  • ???jsp.display-item.citation.pmc??? 584
  • Scopus 1249
  • ???jsp.display-item.citation.isi??? 1173
social impact