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Progress in PARP inhibitors beyond BRCA mutant recurrent ovarian cancer?
Comment
Up to half of newly diagnosed patients with high-grade serous ovarian cancer have a deficit in the homologous recombination system, which repairs double-strand breaks in DNA. Mutations in BRCA1 or BRCA2, which occur in roughly 20% of patients (16% germline and 4% somatic), are the most common cause of homologous recombination deficiency.1 Patients with BRCA mutations have longer overall survival than do patients without such mutations, and their tumours are extremely sensitive to platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors.2 The clinical activity of single-agent PARP inhibitors in patients with BRCA mutations has been widely reported in various disease settings.3,4 However, patients with wild-type BRCA who have homologous recombination deficiency can also respond to PARP inhibition,5 and identification of these patients is a great challenge. The accumulation of genomic damage as a consequence of homologous recombination deficiency can be detected by next-generation sequencing techniques and could potentially help in the selection of patients who are likely to respond to PARP inhibitors.6,7 In The Lancet Oncology, Elizabeth Swisher and colleagues present the results of a single-arm phase 2 trial assessing the ability of a next-generation sequencing assay to detect homologous recombination deficiency as a predictor of response to rucaparib, an oral PARP inhibitor.8 The assay combines somatic BRCA mutation status and the percentage of genome-wide loss of heterogeneity (LOH), with a cutoff point of 14%. Notably, this potential tumour biomarker had an integrated role in the design of the trial and patients were classified into one of three predefined subgroups: BRCA mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). The trial was powered to detect a difference in progression-free survival, assuming that the hazard ratio between each two subgroups was 0·50. The patients included in the trial had epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer, platinum-sensitive relapse, good performance status (133 [65%] of 204 patients had an
Eastern Cooperative Oncology Group performance status of 0), and had received little pretreatment (118 [58%] patients had received only one previous line of therapy). Rucaparib was very active in the BRCA-mutant subgroup, with increased progression-free survival compared with the LOH low subgroup (hazard ratio [HR] 0·27 [95% CI 0·16–0·44, p<0·0001]). Additionally, in the BRCA-mutant subgroup, 32 (80%; 95% CI 64–91) of 40 patients achieved RECIST-confirmed objective responses, median progression-free survival was 12·8 months (95% CI 9·0–14·7), and median response duration was 9·2 months (6·4–12·9). These values compare very well with the expected activity of a platinum-based combination, which is the standard of care for this population. These promising results provide the rationale for the ongoing ARIEL 4 (NCT02855944) randomised phase 3 trial comparing rucaparib versus chemotherapy in patients with BRCA mutations. The most interesting analysis in Swisher and colleagues’ study is the potential predictive value of the LOH assay for rucaparib response in patients without BRCA mutations. Although median progression-free survival was similar between the LOH high and LOH low subgroups (5·7 months [95% CI 5·3–7·6] vs 5·2 months [3·6–5·5]), progression-free survival estimates were significantly longer in the LOH high subgroup compared with the LOH low subgroup (HR 0·62 [95% CI 0·42–0·90, p=0·011]). Additionally, more patients achieved confirmed RECIST responses in the LOH high subgroup (24 [29%; 95% CI 20–40] of 82 patients) than in the LOH low subgroup (7 [10%; 4–20] of 70 patients; p=0·0033), and the duration of response was longer in the LOH high subgroup (10·8 months [95% CI 5·7–not reached]) than in the LOH low subgroup (5·6 months [4·6–8·5]; p=0·022). Two key questions arise with these data: are these results clinically relevant and is the assay efficient enough to identify patients without BRCA mutations who will respond to rucaparib? The proportion of patients achieving objective responses and the median duration of progression-free survival in both BRCA wild-type subgroups (ie, LOH high and LOH low) were inferior to the results expected with a platinum-based combination
www.thelancet.com/oncology Published online November 28, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30621-0
Steve Gschmeissner/Science Photo Library
Progress in PARP inhibitors beyond BRCA mutant recurrent ovarian cancer?
Lancet Oncol 2016 Published Online November 28, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30621-0 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(16)30559-9
1
Comment
in this platinum-sensitive population with little pretreatment, making further comparison of rucaparib monotherapy with platinum-based chemotherapy less attractive. Nevertheless, part two of the ARIEL2 trial (NCT01891344) is including patients who have been more heavily pretreated (at least three previous lines), for whom these results could be more clinically meaningful. With respect to the predictive value of the assay, the differences detected between the LOH high and LOH low subgroups were not particularly clinically relevant and the biomarker does not seem to be able to efficiently identify a subgroup of patients with wild-type BRCA who will achieve significant progression-free survival with rucaparib. In a planned post-hoc analysis of this study,9 Coleman and colleagues showed that a refined cutoff for tumour genomic LOH of 16% is able to better discriminate a difference in progression-free survival between the LOH high and LOH low subgroups than is a cutoff of 14% (HR 0·51 [95% CI 0·34–0·74]; p<0·001). This new cutoff is prospectively applied in the ARIEL 3 trial (NCT01968213), in which patients with high-grade ovarian cancer and platinum-sensitive relapse responding to rechallenge with platinum-based chemotherapy will be randomly assigned to maintenance therapy with rucaparib versus placebo. There are great expectations on the results of this study, because another homologous recombination deficiency assay was shown to be unable to significantly discriminate the efficacy of niraparib in the maintenance setting.10 Finally, this trial constitutes a valuable effort in the challenge of identifying which patients with wild-type
2
BRCA can benefit from PARP inhibition. However, an assay that is efficient and produces clinically meaningful results is still some way off. Antonio González Martín MD Anderson Cancer Center Madrid, Madrid 28033, Spain [email protected] I report fees from Clovis for serving on a local advisory board and fees from Roche, Astra Zenenca, and Pharmamar for being a speaker and advisory board member. 1
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Nielsen FC, van Overeem Hansen T, Sørensen CS. Hereditary breast and ovarian cancer: new genes in confined pathways. Nat Rev Cancer 2016; 16: 599–612. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov 2015; 5: 1137–54. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15: 852–61. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33: 244–50. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12: 852–61. Abkevich V, Timms KM, Hennessy BT, et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 2012; 107: 1776–82. Watkins JA, Irshad S, Grigoriadis A and Tutt AN. Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res 2014, 16: 211 Swisher EM, Lin KK, Oza AM et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncology 2016; published online Nov 28. http://dx.doi.org/10.1016/S1470-2045(16)30559-9. Coleman RL, Swisher EM, Oza AM. Refinement of prespecified cutoff for genomic loss of heterozygosity in ARIEL2 part 1: a phase II study of rucaparib in patients (pts) with high grade ovarian carcinoma. Proc Am Soc Clin Oncol 2016; 34: abstr 5540. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016; published online Oct 7. DOI:10.1056/NEJMoa1611310.
www.thelancet.com/oncology Published online November 28, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30621-0
Up to half of newly diagnosed patients with high-grade serous ovarian cancer have a deficit in the homologous recombination system, which repairs double-strand breaks in DNA. Mutations in BRCA1 or BRCA2, which occur in roughly 20% of patients (16% germline and 4% somatic), are the most common cause of homologous recombination deficiency.1 Patients with BRCA mutations have longer overall survival than do patients without such mutations, and their tumours are extremely sensitive to platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors.2 The clinical activity of single-agent PARP inhibitors in patients with BRCA mutations has been widely reported in various disease settings.3,4 However, patients with wild-type BRCA who have homologous recombination deficiency can also respond to PARP inhibition,5 and identification of these patients is a great challenge. The accumulation of genomic damage as a consequence of homologous recombination deficiency can be detected by next-generation sequencing techniques and could potentially help in the selection of patients who are likely to respond to PARP inhibitors.6,7 In The Lancet Oncology, Elizabeth Swisher and colleagues present the results of a single-arm phase 2 trial assessing the ability of a next-generation sequencing assay to detect homologous recombination deficiency as a predictor of response to rucaparib, an oral PARP inhibitor.8 The assay combines somatic BRCA mutation status and the percentage of genome-wide loss of heterogeneity (LOH), with a cutoff point of 14%. Notably, this potential tumour biomarker had an integrated role in the design of the trial and patients were classified into one of three predefined subgroups: BRCA mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). The trial was powered to detect a difference in progression-free survival, assuming that the hazard ratio between each two subgroups was 0·50. The patients included in the trial had epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer, platinum-sensitive relapse, good performance status (133 [65%] of 204 patients had an
Eastern Cooperative Oncology Group performance status of 0), and had received little pretreatment (118 [58%] patients had received only one previous line of therapy). Rucaparib was very active in the BRCA-mutant subgroup, with increased progression-free survival compared with the LOH low subgroup (hazard ratio [HR] 0·27 [95% CI 0·16–0·44, p<0·0001]). Additionally, in the BRCA-mutant subgroup, 32 (80%; 95% CI 64–91) of 40 patients achieved RECIST-confirmed objective responses, median progression-free survival was 12·8 months (95% CI 9·0–14·7), and median response duration was 9·2 months (6·4–12·9). These values compare very well with the expected activity of a platinum-based combination, which is the standard of care for this population. These promising results provide the rationale for the ongoing ARIEL 4 (NCT02855944) randomised phase 3 trial comparing rucaparib versus chemotherapy in patients with BRCA mutations. The most interesting analysis in Swisher and colleagues’ study is the potential predictive value of the LOH assay for rucaparib response in patients without BRCA mutations. Although median progression-free survival was similar between the LOH high and LOH low subgroups (5·7 months [95% CI 5·3–7·6] vs 5·2 months [3·6–5·5]), progression-free survival estimates were significantly longer in the LOH high subgroup compared with the LOH low subgroup (HR 0·62 [95% CI 0·42–0·90, p=0·011]). Additionally, more patients achieved confirmed RECIST responses in the LOH high subgroup (24 [29%; 95% CI 20–40] of 82 patients) than in the LOH low subgroup (7 [10%; 4–20] of 70 patients; p=0·0033), and the duration of response was longer in the LOH high subgroup (10·8 months [95% CI 5·7–not reached]) than in the LOH low subgroup (5·6 months [4·6–8·5]; p=0·022). Two key questions arise with these data: are these results clinically relevant and is the assay efficient enough to identify patients without BRCA mutations who will respond to rucaparib? The proportion of patients achieving objective responses and the median duration of progression-free survival in both BRCA wild-type subgroups (ie, LOH high and LOH low) were inferior to the results expected with a platinum-based combination
www.thelancet.com/oncology Published online November 28, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30621-0
Steve Gschmeissner/Science Photo Library
Progress in PARP inhibitors beyond BRCA mutant recurrent ovarian cancer?
Lancet Oncol 2016 Published Online November 28, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30621-0 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(16)30559-9
1
Comment
in this platinum-sensitive population with little pretreatment, making further comparison of rucaparib monotherapy with platinum-based chemotherapy less attractive. Nevertheless, part two of the ARIEL2 trial (NCT01891344) is including patients who have been more heavily pretreated (at least three previous lines), for whom these results could be more clinically meaningful. With respect to the predictive value of the assay, the differences detected between the LOH high and LOH low subgroups were not particularly clinically relevant and the biomarker does not seem to be able to efficiently identify a subgroup of patients with wild-type BRCA who will achieve significant progression-free survival with rucaparib. In a planned post-hoc analysis of this study,9 Coleman and colleagues showed that a refined cutoff for tumour genomic LOH of 16% is able to better discriminate a difference in progression-free survival between the LOH high and LOH low subgroups than is a cutoff of 14% (HR 0·51 [95% CI 0·34–0·74]; p<0·001). This new cutoff is prospectively applied in the ARIEL 3 trial (NCT01968213), in which patients with high-grade ovarian cancer and platinum-sensitive relapse responding to rechallenge with platinum-based chemotherapy will be randomly assigned to maintenance therapy with rucaparib versus placebo. There are great expectations on the results of this study, because another homologous recombination deficiency assay was shown to be unable to significantly discriminate the efficacy of niraparib in the maintenance setting.10 Finally, this trial constitutes a valuable effort in the challenge of identifying which patients with wild-type
2
BRCA can benefit from PARP inhibition. However, an assay that is efficient and produces clinically meaningful results is still some way off. Antonio González Martín MD Anderson Cancer Center Madrid, Madrid 28033, Spain [email protected] I report fees from Clovis for serving on a local advisory board and fees from Roche, Astra Zenenca, and Pharmamar for being a speaker and advisory board member. 1
2
3
4
5
6
7
8
9
10
Nielsen FC, van Overeem Hansen T, Sørensen CS. Hereditary breast and ovarian cancer: new genes in confined pathways. Nat Rev Cancer 2016; 16: 599–612. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov 2015; 5: 1137–54. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15: 852–61. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33: 244–50. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12: 852–61. Abkevich V, Timms KM, Hennessy BT, et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 2012; 107: 1776–82. Watkins JA, Irshad S, Grigoriadis A and Tutt AN. Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res 2014, 16: 211 Swisher EM, Lin KK, Oza AM et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncology 2016; published online Nov 28. http://dx.doi.org/10.1016/S1470-2045(16)30559-9. Coleman RL, Swisher EM, Oza AM. Refinement of prespecified cutoff for genomic loss of heterozygosity in ARIEL2 part 1: a phase II study of rucaparib in patients (pts) with high grade ovarian carcinoma. Proc Am Soc Clin Oncol 2016; 34: abstr 5540. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016; published online Oct 7. DOI:10.1056/NEJMoa1611310.
www.thelancet.com/oncology Published online November 28, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30621-0