Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial
Ledermann, J et al., Lancet Oncol. 2016 Nov;17(11):1579-1589
Olaparib is a poly(ADP-ribose) polymerase (PARP) inhibitor that has shown antitumor activity in ovarian cancer, especially tumors with BRCA1/2 mutation (BRCAm). Results from a phase II trial (Study 19) revealed significant improvement in PFS with olaparib maintenance vs. placebo in recurrent platinum sensitive serous ovarian cancer (Lancet Oncol 2014; 15: 852–61). Greatest PFS benefit was observed in the BRCAm subgroup (11.2 mos. vs. 4.3 mos., HR 0.8 [0.10-0.31]; p<0·0001). An updated analysis from this study is summarized below.
- Patients: histologically confirmed recurrent ovarian, fallopian tube, or primary peritoneal cancer with high-grade (grade 2 or 3) serous features or serous component, platinum-sensitive, received at least 2 previous courses of platinum-based chemotherapy with complete or partial response
- Trial design: phase II double-blind, placebo controlled RCT
- Experimental: Olaparib 400 mg PO 2x/day
- Control: Placebo
- Primary: PFS
- Secondary: OS, time to first subsequent therapy or death, time to second subsequent therapy or death, safety
- 265 patients randomized to olaparib (136) and placebo (129)
- Baseline patient characteristics were well balanced in the overall population, BRCAm and BRCA wild type (BRCAwt) subgroups.
- Baseline patient characteristics: > 70% non-Jewish ancestry, >80% primary ovarian cancer, >60% with >12 mos. time to progression after platinum-based chemotherapy, > 50% with partial response to platinum-based chemotherapy
TABLE 1: Efficacy Outcomes
- 15% (10 in each arm) with somatic BRCA mutation (sBRCAm) in the BRCAm subgroup
- 13% (18/136) received olaparib for ≥ 5 yrs.
- Subsequent cancer treatment: 65% olaparib (61% BRCAm) vs. 86% placebo (89% BRCAm)
TABLE 2: Adverse event and treatment summary
- Most common adverse events (≥2 yrs. of treatment): low-grade nausea (75% vs. 40%), fatigue (56% vs. 40%), vomiting (38% vs. 0), anemia (25% vs. 20%)
- Adverse events occurred more frequently during the first 2 yrs. of treatment.
- Similar safety profile was reported for the overall population and BRCA subgroups.
- Most common grade ≥ 3 adverse events: fatigue (8% vs. 3%), anemia (6% vs. 1%)
- No additional deaths reported after 2012 data cutoff.
- Myelodysplastic syndrome or AML (n): olaparib 2 vs. placebo 1
- At a median follow-up of 70 mos., olaparib maintenance significantly improved time to first and second subsequent therapy or death compared to placebo in platinum-sensitive recurrent serous ovarian cancer, with the greatest benefit observed in tumors with BRCAm. Despite the OS trend in favour of olaparib, this was not statistically significant.
- Olaparib maintenance was associated with higher rates of adverse events, resulting in dose reduction and treatment discontinuation. Adverse events were manageable, and most occurred within the first 2 yrs. of treatment. No new safety signals were reported on long-term follow-up.
- The study was not adequately powered for OS analysis. Authors addressed this by conducting Cox proportional hazards analysis, restricted-means analysis, and log-rank test using nominal p values. Although crossover was not allowed, 17 patients in the placebo arm eventually received treatment with PARP inhibitor, potentially confounding study results.
- In summary, olaparib maintenance delayed the onset of subsequent therapy particularly in BRCAm tumors, with a trend towards prolonged overall survival in platinum-resistant recurrent serous ovarian cancer. Although a very small number of patients (11 with BRCAm) continued to benefit with olaparib treatment 5 years and beyond, the cost of prolonged therapy with associated toxicity and lack of survival advantage potentially limits its use in the clinical setting. Results of further phase III studies (SOLO2) are awaited to determine the impact on survival endpoints.
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70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer
Cardoso, F. et al, N Engl J Med. 2016 Aug 25;375(8):717-29
The 70-gene signature (MammaPrint) is a predictive tool that classifies breast tumors as good or poor prognosis based on the risk for distant recurrence at 5 and 10 yrs. After FDA approval for the assay was obtained, Cardoso and colleagues conducted the MINDACT study to determine the clinical utility of the 70-gene signature in addition to clinical pathologic features to determine which patients would benefit with adjuvant chemotherapy.
- Patients: histologically confirmed invasive breast cancer (T1-2 or operable T3), node negative or positive (≤ 3 nodes)
- Study design: phase III RCT
- Prognostic tool 70-gene signature and modified Adjuvant! Online (version 8.0 with HER2 status)
- Low clinical risk definition: 10 yr probability of breast cancer-specific survival without systemic therapy >88% in ER(+) tumors and >92% in ER (-) tumors.
- Low risk – no systemic chemotherapy
- High risk in both 70-gene assay and Adjuvant! Online – systemic chemotherapy
- Discordant results (high clinical risk or low genomic risk or vise versa) – randomized to chemotherapy or no chemotherapy based on either clinical or genomic result
- * adjuvant chemotherapy group could be further randomized to either anthracycline-based regimen or docetaxel-capecitabine ER positive patients could be further randomized to either tamoxifen followed by letrozole or letrozole alone.
- Primary: 5 yr. EFS (Event Free survival: survival without distant metastasis)
- Secondary: proportion of patients who received chemotherapy based on clinical vs. genomic risk, OS, DFS
- 6,693 patients enrolled; low clinical and genomic risk 2,475 (41%), low clinical and high genomic risk 592 (8.8%), high clinical and low genomic risk 1,550 (23.2%), high clinical and genomic risk 1,806 (27%)
- ITT: 1,550 high clinical and low genomic risk patients randomized to chemo (n=749) vs. no chemo (n=748)
- Baseline patient characteristics: median age 55 yrs., 65.9% 50-70 yrs. old, 57.9% 1-2 cm. tumor, 49.1% grade 2, 79% node negative, 20.9% 1-3 positive lymph nodes, 88.4% ER/PR positive, 90.3% HER2 negative, 0.5% HER2 positive, 80.7% luminal HER2 negative, ER/PR positive, 96.1% PS 0
- Chemotherapy vs. no chemotherapy
TABLE 1: Outcomes for chemo vs. no chemo (ITT population)
- No difference in DFS and OS between chemotherapy vs. no chemotherapy was noted in the discordant group for both high clinical, low genomic risk and low clinical, high genomic risk.
TABLE 2: Outcomes in Discordant Risk Group (Per protocol population)
- Clinical vs. genomic risk
- 3,356 patients with high clinical risk (1,550 low genomic risk, 1,806 high genomic risk)
- 2,398 patients with high genomic risk (592 low clinical risk, 1,806 high clinical risk)
- Difference between clinical vs. genomic risk strategy for 6,693 patients: 958 (14.3%)
- For all high clinical risk patients, 70-gene signature used as a guide for chemotherapy treatment decreased the use of chemotherapy in 46.2% (1,550/3,356).
- Chemotherapy decision based on either clinical or genomic risk alone
- 5-yr. EFS by clinical strategy alone 95% vs. genomic risk alone 94.7%
TABLE 3: Analysis in high clinical, low genomic risk subgroup by nodal status
- Multivariate analysis revealed significant association between 70-gene signature and EFS (HR for chemo vs. no chemo 2.41; p<0.001).
- At a median follow-up of 5 yrs., the MINDACT study revealed that patients with early breast cancer with high clinical risk but low genomic risk for recurrence using the 70-gene signature could avoid adjuvant chemotherapy. The 70-gene signature assay reduced the use of chemotherapy in 46.2% of high clinical risk patients.
- Among the high clinical and low genomic risk patients, 5-yr. EFS or survival free from distant metastasis was comparable between chemotherapy and no chemotherapy. In the ITT population, there was again no significant difference in DFS and OS as well as EFS for the low clinical and high genomic subgroup with chemotherapy vs. no chemotherapy.
- Study limitations include the use of a modified version of Adjuvant! Online to predict clinical risk and protocol revision due to a change in RNA extraction solution that required recalibration, and was adjusted for using "corrected risk" and sample size recalculation. This study does not provide evidence for recommendations for patients with low clinical risk. Recurrence risk in hormone positive breast cancer continues beyond 5 yrs. so data collection is currently ongoing for planned 10-yr. analysis.
- In summary, this study suggests that women with early breast cancer with high clinical and low genomic risk on the 70-gene signature assay who forego adjuvant chemotherapy have a comparable 5-yr. distant metastasis-free survival with those who receive adjuvant chemotherapy. The use of the 70-gene signature in combination with clinically pathological features could spare many patients from chemotherapy-associated acute and long-term side effects and significantly reduce the cost of cancer treatment. Longer follow-up is needed to provide evidence on whether this strategy will not compromise the risk for future relapse.
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