Olaparib in the management of ovarian cancer

Figures & data

Figure 1 Dual mechanism of action of PARPi.

Notes: Olaparib inhibits parylation by competing with the binding of NAD⁺ to PARP1, PARP2, and PARP3. Additionally, olaparib traps PARP1 and PARP2 on DNA therefore interfering with DNA damage repair and ultimately leading to cytotoxicity.
Abbreviations: PARPi, poly(ADP-ribose) polymerase inhibitor; NAD⁺, nicotina-mide adenine dinucleotide.

Table 1 Olaparib monotherapy for the treatment of recurrent ovarian cancer

Trial	Study design	Eligibility	Study arms	Primary endpoint	Results
Audeh et al^Citation48	Phase II	– Recurrent OvCa – gBRCA mutation – Measurable disease – >1 prior	1. Olaparib 400 mg bid (n=33) 2.Olaparib 100 mg bid (n=24)	ORR	ORR 33% vs 13% SD 36% vs 29% PFS 5.8 mo vs 1.9 mo
Gelmon et al^Citation49	Phase II	– Metastatic/recurrent BrCa (triple negative) or OvCa (HGSC, poorly differentiated CA, and/or gBRCA mutation with any histology)	1. Olaparib 400 mg bid (ovarian cancer cohort, n=64)	ORR	ORR (OvCa): 29% gBRCA mutation: 41% BRCA wt: 24% Disease control rate (OvCa): 66% gBRCA mutation: 62% BRCA wt: 62% Median PFS (OvCa): 7.3 mo gBRCA mutation: 7.4 mo BRCA wt: 6.4 mo
Kaye et al^Citation50	Randomized Phase II	– Recurrent OvCa – Platinum sensitive, <12 mo since prior platinum therapy – Germline BRCA mutation	1. Olaparib 200 mg PO bid (n=32) 2. Olaparib 400 mg PO bid (n=32) 3. PLD 50 mg/m^2 IV q28d (n=33) Crossover permitted	PFS	PFS: 6.5 mo vs 8.8 mo vs 7.1 mo ORR: 25% vs 31% vs 18% SD: 47% vs 59% vs 52% Median DOR: 6.0 mo vs 6.8 mo vs 5.5 mo
Kaufman et al^Citation52	Phase II	– Advanced solid tumor (including recurrent OvCa) – Platinum resistant – gBRCA mutation – Measurable/evaluable disease	1. Olaparib 400 mg bid (n=298)	TRR	TRR: 26.2% (31.1% OvCa) ORR: 29.3% SD: 41.6% (40.4% OvCa) Median PFS (OvCa): 7 mo Median OS (OvCa): 16.6 mo
Ledermann et al^Citation51,Citation68 (Study 19)	Randomized Phase II	– Recurrent OvCa (serous) – Platinum sensitive – >Two courses of platinum-based chemo – ± Germline BRCA mutation	1. Olaparib 400 mg PO bid (n=136) 2. Placebo (n=129)	PFS	PFS: 8.4 mo vs 4.8 mo* gBRCA mutation: 11.2 mo vs 4.3 mo* BRCA wt: 7.4 mo vs 5.5 mo* OS: 29.8 mo vs 27.8 gBRCA mutation: 34.9 vs 31.9 BRCA wt: 24.5 vs 26.2

Note:

* P<0.05.

Abbreviations: ORR, overall response rate; mo, months; SD, stable disease; PFS, progression-free survival; DOR, duration of response; TRR, tumor response rate; OS, overall survival; PLD, pegylated liposomal doxorubicin; PO, mouth; bid, twice daily; IV, intravenously; HGSC, high grade serous carcinoma; OvCa, ovarian cancer; q28d, every 28 days; BrCa, breast cancer.

Table 2 Olaparib in combination therapy for the treatment of recurrent ovarian cancer

Trial	Study design	Eligibility	Study arms	Primary endpoint	Results
Liu et al^Citation54	Phase I	– Recurrent OvCa or metastatic triple negative BrCa – Measurable disease – Prior platinum (OvCa) – ± gBRCA mutation	Olaparib PO bid + cediranib PO daily (dose escalation) (n=28 [20 OvCa])	MTD/DLT	ORR: 44% (OvCa) CBR: 61% (OvCa) Median PFS: 8.7 mo (OvCa)
Liu et al^Citation55	Randomized Phase II	– Recurrent OvCa – HGSC or endometrioid histology(any histology if gBRCA mutation) – Platinum sensitive – Measurable disease	1 Olaparib 400 mg PO bid (n=46) 2. Olaparib 200 mg bid + cediranib 30 mg daily (n=44)	PFS	PFS: 9.0 mo vs 17.7 mo* BRCA wt: 5.7 mo vs 16.5 mo* ORR: 47.8% vs 79.6%* BRCA wt: 32% vs 76%* 2 years OS: 65% vs 81%
Del Conte en al^Citation59	Phase I	– Advanced solid tumors – <Three prior lines of chemo – ± gBRCA mutation	PLD 40 mg/m^2 q 28 days + olaparib (continuous vs intermittent, dose escalation) (n=44 [28 OvCa])	MTD/DLT	MTD not reached ORR 50% (OvCa)
Lee et al^Citation60	Phase I/Ib	– BRCA germline mutation or BRCAPro score >30% – Recurrent/advanced breast/ovarian cancer – Measurable – No platinum >6 mo	Carboplatin + olaparib PO bid (100–400 mg bid) × eight cycles → olaparib maintenance therapy (n=45 [37 OvCa])	DLT	ORR: 44.1% (OvCa) ORR platinum sensitive: 71.4% ORR platinum resistant: 25% CBR: 82.3% (OvCa)
Oza et al^Citation61	Randomized Phase II	– Recurrent HGSC – Platinum sensitive – <Three lines of platinum-based chemo – Measurable disease – ± gBRCA mutation	1 Carboplatin/paclitaxel + olaparib 200 mg PO bid (d1–10) → olaparib 400 mg PO bid (n=81) 2 Carboplatin/paclitaxel (n=81)	PFS	PFS: 12.2 mo vs 9.6 mo* OS: 33.8 mo vs 37.6 mo ORR: 64% vs 58%

Note:

* P<0.05.

Abbreviations: MTD, maximum tolerated dose; DLT, dose-limiting toxicity; mo, months; ORR, overall response rate; CBR, clinical benefit rate; PFS, progression-free survival; OS, overall survival; PLD, pegylated liposomal doxorubicin; PO, mouth; bid, twice daily; HGSC, high grade serous carcinoma; OvCa, ovarian cancer; BrCa, breast cancer.

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