Multicentre Study of Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed Non gBRCAm Ovarian Cancer Patients

Maintenance monotherapy with the potent polyadenosine 5'diphosphoribose \[Poly (ADP-ribose)\] polymerisation (PARP) inhibitor (PARPi) olaparib will significantly prolong progression-free survival (PFS) in platinum sensitive relapsed non-germline breast cancer susceptibility gene (BRCA) mutated ovarian cancer patients who are in complete or partial response following platinum based chemotherapy.

Olaparib is a potent PARPi (PARP-1, -2 and -3) that is being developed as an oral therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy and other anticancer agents. PARP inhibition is a novel approach to targeting tumours with deficiencies in DNA repair mechanisms. PARP enzymes are essential for repairing DNA single strand breaks (SSBs). Inhibiting PARP enzymes leads to the persistence of SSBs, which are then converted to the more serious DNA double strand breaks (DSBs) during the process of DNA replication. During the process of cell division, DSBs can be efficiently repaired in normal cells by homologous recombination (HR) repair. Tumours with HR deficiencies (HRDs), such as ovarian cancers in patients with BRCA1/2 mutations, cannot accurately repair the DNA damage, which may become lethal to cells as it accumulates. In such tumour types, olaparib may offer a potentially efficacious and less toxic cancer treatment compared with currently available chemotherapy regimens.

While multiple randomized controlled trials (RCTs) have demonstrated that platinum sensitive BRCAm patients have profound response to maintenance treatment with PARP inhibitors, PARP inhibitors target cells with homologous recombination deficiency (HRD), of which BRCA mutation is only one type. Consistent with the mechanism of action of PARP inhibition, response has also been seen in multiple RCTs in patients who are platinum sensitive but whose tumours do not harbor BRCA mutations. Presumably these responders have defects in other components of HRR pathways, though currently available diagnostic technology is not adequate to reliably identify the full spectrum of HRR deficiencies. Instead, these data support the hypothesis that platinum sensitivity itself is a clinical selection factor for HRD.

• Olaparib (Drug), also known as Lynparza: 300 mg twice daily - oral

Primary outcomes

• Progression Free Survival (PFS) [Up to maximum of 32 months]: PFS is defined as the time from date of first dose until the date of objective radiological disease progression. Assessed according to modified Response Evaluation Criteria In Solid Tumours Version 1.1 (RECIST 1.1) or death (by any cause in the absence of progression). Progression was determined by investigator assessment, RECIST 1.1. Calculated using the Kaplan-Meier technique. Confidence intervals (CI) for median PFS was derived based on Brookmeyer-Crowley method.

Secondary outcomes

• Time to First Subsequent Therapy or Death (TFST) [Up to a maximum of 43 months]: TFST is defined as the time from date of first dose to date of first subsequent treatment commencement or death due to any cause if this occurs before commencement of first subsequent treatment. Calculated using the Kaplan-Meier technique. CI for median TFST was derived based on Brookmeyer-Crowley method.
• Time to Treatment Discontinuation or Death (TDT) [Up to a maximum of 43 months]: TDT is defined as the time from date of first dose to date of study drug discontinuation or death due to any cause if this occurs before study drug discontinuation. Calculated using the Kaplan-Meier technique. CI for median TDT was derived based on Brookmeyer-Crowley method.
• PFS by Homologous Recombination Deficiency (HRD)/ Breast Cancer Susceptibility Gene Mutation (Mutated) (BRCAm) Status [Up to maximum of 32 months]: HRD/BRCAm status was based on the central blood and tumour assessments. Assessed according to modified RECIST 1.1 or death (by any cause in the absence of progression). Progression was determined by investigator assessment, RECIST 1.1. Calculated using the Kaplan-Meier technique. CI for median PFS was derived based on Brookmeyer-Crowley method.
• Chemotherapy-free Interval (CT-FI) [Up to a maximum of 43 months]: CT-FI is defined as the time from the date of the last dose of platinum chemotherapy prior to olaparib maintenance therapy until the date of initiation of the next anticancer therapy. Calculated using the Kaplan-Meier technique. CI for median CT-FI was derived based on Brookmeyer-Crowley method.
• Overall Survival (OS) [Up to a maximum of 43 months]: OS is defined as the time from the date of first dose of olaparib to the date of death from any cause. Calculated using the Kaplan-Meier technique. CI for median OS was derived based on Brookmeyer-Crowley method.
• Percentage of Patients With Any Improvement From Baseline in Trial Outcome Index (TOI) Score at Any Point During the Treatment Period [Baseline up to a maximum of 32 months]: Improvement was defined as a functional assessment of cancer therapy - ovarian (FACT-O) TOI response of "any improvement" at any time point over the course of treatment. The TOI is an established single targeted index composed of the following scales of the FACT-O: physical and functional well-being and additional concerns. The range of possible scores for the FACT-O TOI is 0-100, with a higher score indicating better health related quality of life (HRQoL). An increase in score from baseline indicates an improvement in HRQoL.
• Percentage of Patients With a 10-Point Deterioration From Baseline in TOI Score at Any Point During the Treatment Period [Baseline up to a maximum of 32 months]: 10-point deterioration was defined as a FACT-O TOI response of "10-point deterioration" at any time point over the course of treatment. The TOI is an established single targeted index composed of the following scales of the FACT-O: physical and functional well-being and additional concerns. The range of possible scores for the FACT-O TOI is 0-100, with a higher score indicating better HRQoL. A decrease in score of at least 10 points from baseline was defined as a clinically meaningful deterioration.

Sex: Female, ages: 18 Years to 95 Years

Key Inclusion Criteria:

* Female patients with histologically diagnosed relapsed HGSOC (including primary peritoneal and / or fallopian tube cancer) or high grade endometrioid ovarian cancer
* Documented gBRCA1/2 mutation status
* Patients must have completed at least 2 previous courses of platinum containing therapy
* Patients must have normal organ and bone marrow function measured within 28 days of starting study treatment
* ECOG performance status 0-1 (see Appendix E)
* Patients must have a life expectancy ≥16 weeks
* Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1
* At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline with computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for repeated assessment OR No evidence of disease following a complete response to chemotherapy
* An appropriately prepared tumour sample from the cancer, of sufficient quantity and quality (as specified in the Central Laboratory Services Manual) must be available for future central testing of tumour genetic status

Exclusion Criteria:

* Patients receiving any systemic hormonal therapy, chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to start of study treatment
* Any previous treatment with PARP inhibitor, including olaparib
* Patients with a germline BRCA mutation that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental / lead to loss of function)
* Other malignancy unless curatively treated with no evidence of disease for ≥5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma.
* Concomitant use of known strong CYP3A inhibitors and strong (or moderate CYP3A inducers
* Persistent toxicities (≥ Grade 2 Common Terminology Criteria for Adverse Event (CTCAE) adverse event) caused by previous cancer therapy, excluding alopecia
* Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML
* Patients with symptomatic uncontrolled brain metastases

Participant flow

Outcome results

• Progression Free Survival (PFS) (Primary), Median, months: Olaparib 9.2 (7.6 to 10.9)
• Time to First Subsequent Therapy or Death (TFST) (Secondary), Median, months: Olaparib 13.9 (11.5 to 16.6)
• Time to Treatment Discontinuation or Death (TDT) (Secondary), Median, months: Olaparib 9.6 (7.8 to 11.1)
• PFS by Homologous Recombination Deficiency (HRD)/ Breast Cancer Susceptibility Gene Mutation (Mutated) (BRCAm) Status (Secondary), Median, months: Olaparib 11.1 (9.2 to 14.6)
• Chemotherapy-free Interval (CT-FI) (Secondary), Median, months: Olaparib 17.9 (13.8 to 23.3)
• Overall Survival (OS) (Secondary), Median, months: Olaparib 32.7 (29.5 to 35.3)
• Percentage of Patients With Any Improvement From Baseline in Trial Outcome Index (TOI) Score at Any Point During the Treatment Period (Secondary), Number, percentage of patients: Olaparib 64.3 (58.0 to 70.2)
• Percentage of Patients With a 10-Point Deterioration From Baseline in TOI Score at Any Point During the Treatment Period (Secondary), Number, percentage of patients: Olaparib 42.6 (36.3 to 49.0)

Adverse events

Time frame: Includes adverse events with an onset date on or after the date of first dose and up to and including 30 days following the date of last dose of olaparib, up to a maximum of 43 months

Serious adverse events by term

Other adverse events by term

294 more terms not shown.

• Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009 Jul 9;361(2):123-34. doi: 10.1056/NEJMoa0900212. Epub 2009 Jun 24. PMID 19553641
• Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, Derksen PW, de Bruin M, Zevenhoven J, Lau A, Boulter R, Cranston A, O'Connor MJ, Martin NM, Borst P, Jonkers J. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17079-84. doi: 10.1073/pnas.0806092105. Epub 2008 Oct 29. PMID 18971340
• Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res. 2012 Nov 1;72(21):5588-99. doi: 10.1158/0008-5472.CAN-12-2753. PMID 23118055
• Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, Ledermann JA, Lorusso D, Vergote I, Ben-Baruch NE, Marth C, Madry R, Christensen RD, Berek JS, Dorum A, Tinker AV, du Bois A, Gonzalez-Martin A, Follana P, Benigno B, Rosenberg P, Gilbert L, Rimel BJ, Buscema J, Balser JP, Agarwal S, Matulonis UA; ENGOT-OV16/NOVA Investigators. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016 Dec 1;375(22):2154-2164. doi: 10.1056/NEJMoa1611310. Epub 2016 Oct 7. PMID 27717299
• Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol. 2011 Aug;5(4):387-93. doi: 10.1016/j.molonc.2011.07.001. Epub 2011 Jul 22. PMID 21821475
• Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, Douglas-Jones A, Smith GC, Martin NM, O'Connor M, Clarke AR. Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 2009 May 1;69(9):3850-5. doi: 10.1158/0008-5472.CAN-08-2388. Epub 2009 Apr 21. PMID 19383921
• Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012 Apr 12;366(15):1382-92. doi: 10.1056/NEJMoa1105535. Epub 2012 Mar 27. PMID 22452356
• Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, Korach J, Huzarski T, Poveda A, Pignata S, Friedlander M, Colombo N, Harter P, Fujiwara K, Ray-Coquard I, Banerjee S, Liu J, Lowe ES, Bloomfield R, Pautier P; SOLO2/ENGOT-Ov21 investigators. 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. Lancet Oncol. 2017 Sep;18(9):1274-1284. doi: 10.1016/S1470-2045(17)30469-2. Epub 2017 Jul 25. PMID 28754483
• Results publication: Barnicle A, Ray-Coquard I, Rouleau E, Cadoo K, Simpkins F, Aghajanian C, Leary A, Poveda A, Lheureux S, Pujade-Lauraine E, You B, Ledermann J, Matulonis U, Gourley C, Timms KM, Lai Z, Hodgson DR, Elks CE, Dearden S, Egile C, Lao-Sirieix P, Harrington EA, Brown JS. Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib. Genome Med. 2024 Dec 18;16(1):145. doi: 10.1186/s13073-024-01413-5. PMID 39695768
• Results publication: Poveda A, Lheureux S, Colombo N, Cibula D, Lindemann K, Weberpals J, Bjurberg M, Oaknin A, Sikorska M, Gonzalez-Martin A, Madry R, Perez MJR, Ledermann J, Davidson R, Blakeley C, Bennett J, Barnicle A, Skof E. Olaparib maintenance monotherapy in platinum-sensitive relapsed ovarian cancer patients without a germline BRCA1/BRCA2 mutation: OPINION primary analysis. Gynecol Oncol. 2022 Mar;164(3):498-504. doi: 10.1016/j.ygyno.2021.12.025. Epub 2022 Jan 19. PMID 35063276
• Results publication: Poveda AM, Davidson R, Blakeley C, Milner A. Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design. Future Oncol. 2019 Nov;15(32):3651-3663. doi: 10.2217/fon-2019-0343. Epub 2019 Sep 25. PMID 31553234

• Study Protocol (PDF, 2018-10-26)
• Statistical Analysis Plan (PDF, 2019-12-09)

• Chris Wilks, Study director, AstraZeneca

NIH grants: 2017