A Pan-Canadian Consensus Statement on First-Line PARP Inhibitor Maintenance for Advanced, High-Grade Serous and Endometrioid Tubal, Ovarian, and Primary Peritoneal Cancers
Abstract
:1. Introduction
2. Consensus Process
3. Genetic Testing to Inform PARP Inhibitor Maintenance Strategies
3.1. Consensus Statements
- (a)
- All patients with high-grade EOC should have BRCA1/2 mutation testing to:
- i.
- Inform hereditary cancer predisposition and the need for cascade testing of family members;
- ii.
- Guide first-line PARP inhibitor maintenance in advanced stage cases.
- (b)
- Tumour HRD status is a predictive biomarker of treatment benefit from PARP inhibitors, and testing should be publicly funded.
- (c)
- Assessment of mutations in HRR genes other than BRCA1/2 should not be used as a substitute for HRD testing.
3.2. Summary of Evidence
3.3. Interpretation and Canadian Perspective
4. Selection of PARP Inhibitors as First-Line Maintenance Therapy in Advanced EOC
4.1. Consensus Statements
- (d)
- All BRCA1/2-mutated patients with advanced EOC should receive maintenance therapy with a PARP inhibitor following a response to platinum-based chemotherapy. The choice of PARP inhibitor is influenced by several factors, including the expected toxicity profile of each agent.
- (e)
- Patients with advanced EOC who are BRCA1/2 wild-type and have responded to platinum-based chemotherapy should be considered for maintenance treatment with niraparib.
- (f)
- There is evidence to support the combination of olaparib with bevacizumab as a maintenance regimen in patients with advanced, high-grade, HRD-positive EOC who respond to first-line treatment with platinum chemotherapy and bevacizumab.
4.2. Summary of Evidence
4.3. Interpretation and Canadian Perspective
5. Dosing and Duration of PARP Inhibitor Maintenance Therapy
5.1. Consensus Statements
- (g)
- Olaparib should be given orally at a starting dose of 300 mg, twice-daily for up to two years in patients with a response to first-line platinum-based chemotherapy. Treatment beyond 2 years should only be considered in patients who have evidence of disease at the 2-year time point for whom ongoing treatment is felt to be beneficial.
- (h)
- Niraparib should be given orally at a starting dose of 200 mg, once-daily for patients weighing less than 77 kg or with a platelet count of less than 150,000/µL, or at a starting dose of 300 mg, once-daily for patients weighing greater than or equal to 77 kg and with a platelet count of greater than or equal to 150,000/µL. Treatment beyond 3 years should only be considered in patients who have evidence of disease at the 3-year time point for whom ongoing treatment is felt to be beneficial.
- (i)
- Patients should be informed of the expected treatment duration and data to support completion of treatment at the time of maintenance therapy initiation.
- (j)
- Routine clinical assessments and laboratory monitoring are required, for the duration of therapy, taking into consideration the common adverse events.
- (k)
- Toxicities can be managed through dose interruptions and reductions as described in the product monograph for each PARP inhibitor, followed by a rechallenge upon resolution of toxicity.
- (l)
- Switching between approved PARP inhibitors in the first-line maintenance setting for unmanageable toxicity is considered a reasonable option to allow for the continuation of PARP inhibitor therapy.
5.2. Summary of Evidence
5.3. Interpretation and Canadian Perspective
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Genetic Testing to Inform PARP Inhibitor Maintenance Strategies |
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Selection of PARP inhibitors as first-line maintenance therapy in advanced EOC |
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Dosing and duration of PARPi maintenance therapy |
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Trial Name, Study Phase | Treatment Arms | Study Population | HRD Testing Method | PFS Results (PARP Inhibitor vs. Control) | ||
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Population | Median (Months) | HR (95% CI) | ||||
SOLO-1 [8] (NCT01844986) Phase III | olaparib vs. placebo | Stage III/IV BRCAm EOC following PR/CR to CT | N/A | BRACm(ITT) | 56.0 vs. 13.8 | 0.33 (0.25–0.43) |
PRIMA [9] (NCT02655016) Phase III | niraparib vs. placebo | Stage III/IV high-risk EOC with visible residual disease following PR/CR to CT | Myriad myChoice CDx (HRD = GIS ≥ 42 or BRCA1/2 mutation) | ITT | 13.8 vs. 8.2 | 0.62 (0.50–0.76) |
HRD | 21.9 vs. 10.4 | 0.43 (0.31–0.59) | ||||
BRCAm | 22.1 vs. 10.9 | 0.40 (0.27–0.62) | ||||
HRD/BRCAwt | 19.6 vs. 8.2 | 0.50 (0.31–0.83) | ||||
HRP | 8.1 vs. 5.4 | 0.68 (0.49–0.94) | ||||
PAOLA1 * [44] (NCT02477644) Phase III | olaparib + bevacizumab vs. placebo + bevacizumab | Stage III/IV EOC following PR/CR to CT + bevacizumab | Myriad myChoice CDx (HRD = GIS ≥ 42 or BRCA1/2 mutation) | ITT | 22.1 vs. 16.6 | 0.59 (0.49–0.72) |
HRD | 37.2 vs.17.7 | 0.33 (0.25–0.45) | ||||
BRCAm | 37.2 vs. 21.7 | 0.31 (0.20–0.47) | ||||
HRD/BRCAwt | 28.1 vs. 16.6 | 0.43 (0.28–0.66) | ||||
HRP/HRnd | 16.9 vs. 16.0 | 0.92 (0.72–1.17) | ||||
VELIA *,†,‡ [50] (NCT02470585) Phase III | CT + veliparib → veliparib vs. CT + 66veliparib → placebo vs. CT + placebo → placebo | Stage III/IV high-grade serous ovarian carcinoma | Myriad myChoice CDx (HRD = GIS ≥ 33 or BRCA1/2 mutation) | ITT | 23.5 vs. 17.3 | 0.68 (0.56–0.83) |
HRD | 31.9 vs. 20.5 | 0.57 (0.43–0.76) | ||||
BRCAm | 34.7 vs. 22.0 | 0.44 (0.28–0.68) | ||||
BRCAwt | 18.2 vs. 15.1 | 0.80 (0.64–1.00) | ||||
HRP | 15.0 vs. 11.5 | 0.81 (0.60–1.09) |
Study Attribute | SOLO-1 (N = 391) | PRIMA (N = 733) |
---|---|---|
Design | International, randomized (2:1), double-blind | |
Treatment arms | Olaparib vs. placebo | Niraparib vs. placebo |
Dosing | Olaparib 300 mg twice-daily up to 24 months or until progression for patients in PR | Niraparib 300 mg once-daily * up to 36 months (or until progression for patients in PR) |
Eligibility criteria | BRCA1/2 mutated No prior bevacizumab Stage III/IV CR/PR to platinum-CT | Stage III inoperable/visible residual disease and stage IV † CR/PR to platinum-CT |
Stage IV | 17% | 35% |
PDS/NACT-IDS | 63%/35% | 32%/67% |
NED or CR after platinum-CT | 74% | 69% |
BRCA1/2 mutated | 100% | 30% |
HRD testing | None | Myriad myChoice HRD GIS score ≥ 42 or BRCA1/2 mutation |
Primary endpoint | PFS Investigator-assessed | PFS Blinded Independent central review HRD and ITT (Hierarchical testing) |
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Tinker, A.V.; Altman, A.D.; Bernardini, M.Q.; Ghatage, P.; Gien, L.T.; Provencher, D.; Salvador, S.; Doucette, S.; Oza, A.M. A Pan-Canadian Consensus Statement on First-Line PARP Inhibitor Maintenance for Advanced, High-Grade Serous and Endometrioid Tubal, Ovarian, and Primary Peritoneal Cancers. Curr. Oncol. 2022, 29, 4354-4369. https://doi.org/10.3390/curroncol29060348
Tinker AV, Altman AD, Bernardini MQ, Ghatage P, Gien LT, Provencher D, Salvador S, Doucette S, Oza AM. A Pan-Canadian Consensus Statement on First-Line PARP Inhibitor Maintenance for Advanced, High-Grade Serous and Endometrioid Tubal, Ovarian, and Primary Peritoneal Cancers. Current Oncology. 2022; 29(6):4354-4369. https://doi.org/10.3390/curroncol29060348
Chicago/Turabian StyleTinker, Anna V., Alon D. Altman, Marcus Q. Bernardini, Prafull Ghatage, Lilian T. Gien, Diane Provencher, Shannon Salvador, Sarah Doucette, and Amit M. Oza. 2022. "A Pan-Canadian Consensus Statement on First-Line PARP Inhibitor Maintenance for Advanced, High-Grade Serous and Endometrioid Tubal, Ovarian, and Primary Peritoneal Cancers" Current Oncology 29, no. 6: 4354-4369. https://doi.org/10.3390/curroncol29060348