Olaparib (Lynparza®): A Comprehensive Clinical and Pharmacological Monograph

I. Executive Summary

Olaparib, marketed as Lynparza®, is a first-in-class, orally administered small molecule inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes. It represents a paradigm of targeted therapy, leveraging the principle of synthetic lethality to selectively induce cytotoxicity in tumors with deficiencies in the homologous recombination repair (HRR) pathway, most notably those with deleterious BRCA1 or BRCA2 mutations. This mechanism provides a wide therapeutic index, effectively targeting cancer cells while relatively sparing normal cells.

The drug has secured landmark approvals from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of specific, biomarker-defined patient populations across four major cancer types: ovarian, breast, prostate, and pancreatic cancer.[1] Its indications have evolved significantly, moving from late-line salvage therapy for heavily pre-treated patients to first-line maintenance and adjuvant settings, fundamentally altering the standards of care for eligible individuals.[2]

The clinical efficacy of Olaparib is supported by a robust portfolio of pivotal Phase III trials. Studies such as SOLO-1, SOLO-2, and PAOLA-1 in ovarian cancer; OlympiA in early breast cancer; PROfound in prostate cancer; and POLO in pancreatic cancer have consistently demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS).[4] In certain settings, particularly the adjuvant treatment of early breast cancer, this has translated into a significant overall survival (OS) benefit, establishing Olaparib as a cornerstone of care for patients with susceptible tumors.[7]

The safety profile of Olaparib is well-characterized. The most common adverse reactions include nausea, fatigue, and hematological toxicities such as anemia and neutropenia.[2] While generally manageable through supportive care and dose modifications, serious risks have been identified, including myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), pneumonitis, and venous thromboembolism (VTE).[12] The heavy reliance on CYP3A4 for metabolism also necessitates careful management of drug-drug interactions.[15]

Olaparib has transformed the management of HRR-deficient cancers and has underscored the critical importance of routine genomic testing in oncologic practice. Its development and successful clinical application serve as a premier example of bench-to-bedside translational research. Ongoing studies continue to explore its utility in new combinations, additional tumor types, and strategies to overcome acquired resistance, promising to further expand its role in precision oncology.

II. Introduction: The Advent of Synthetic Lethality in Oncology

The development of Olaparib is a landmark achievement in the history of targeted cancer therapy, representing the clinical validation of a fundamental biological concept: synthetic lethality. This journey began not with the drug itself, but with foundational research into the genetic underpinnings of hereditary cancer. The discovery of the BRCA1 and BRCA2 tumor suppressor genes in the mid-1990s was a critical first step, identifying their crucial role in maintaining genomic stability by repairing DNA double-strand breaks (DSBs) through the high-fidelity homologous recombination (HR) pathway.[17] A deficiency in this pathway, common in cancers arising in individuals with germline

BRCA mutations, leaves cells vulnerable to DNA damage.

The pivotal intellectual leap occurred when researchers hypothesized that cancer cells with a pre-existing defect in the HR pathway would become uniquely dependent on other, parallel DNA repair mechanisms for survival.[17] One such pathway is the base excision repair (BER) system, which repairs DNA single-strand breaks (SSBs) and is critically mediated by poly(ADP-ribose) polymerase (PARP) enzymes.[1] The concept of synthetic lethality posits that while the loss of either the HR pathway or the PARP-mediated pathway alone is compatible with cell viability, the simultaneous loss of both is catastrophic, leading to overwhelming DNA damage and selective cell death.[20] Normal, healthy cells, which possess a functional HR pathway, can tolerate the inhibition of PARP and repair the resulting DSBs, thus creating a therapeutic window to specifically target cancer cells.[3]

This hypothesis was validated in seminal preclinical studies in 2005, which showed that PARP inhibitors could selectively kill cancer cells with BRCA mutations.[18] This discovery provided the scientific rationale for developing PARP inhibitors not as chemo- or radiosensitizers, but as single-agent therapies for biomarker-selected tumors. Olaparib, originally known as KU-0059436, emerged from this research at KuDOS Pharmaceuticals, a UK-based company founded by Professor Steve Jackson of Cambridge University.[3] The first-in-human clinical trial of Olaparib began in 2005, providing early proof-of-concept by demonstrating both a manageable safety profile and promising anti-tumor activity in patients with

BRCA-mutated cancers.[3]

Following the acquisition of KuDOS by AstraZeneca in 2006, and later a global strategic collaboration with Merck & Co., Inc. (MSD) in 2017, Olaparib underwent extensive clinical development.[3] This journey from a fundamental biological insight to a globally approved, practice-changing drug exemplifies the power of translational science. It has not only provided a new class of therapy for patients but has also established a blueprint for future drug development, demonstrating that targeting the intrinsic vulnerabilities of cancer cells can yield highly effective treatments that move beyond the paradigm of broadly cytotoxic chemotherapy.

III. Molecular Profile and Pharmacology

A comprehensive understanding of Olaparib's efficacy and safety begins with its fundamental molecular properties, its precise mechanism of action, and its pharmacokinetic behavior in the human body.

3.1 Chemical and Physical Properties

Olaparib is a synthetic, orally available small molecule.[1] Its chemical and physical characteristics are well-defined across multiple databases and research publications.

• Nomenclature: The drug is known by its generic name, Olaparib, and is marketed globally under the brand name Lynparza®.[1] During its development, it was referred to by the code names AZD-2281 and KU-0059436.[29]
• Chemical Identity: Its systematic IUPAC name is 4-[[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one.[29] The molecule is classified as an N-acylpiperazine, a member of cyclopropanes, monofluorobenzenes, and phthalazines.[29]
• Physicochemical Data: Olaparib has a chemical formula of C24​H23​FN4​O3​ and an average molecular weight of approximately 434.46 g/mol.[1] In its solid state, it is described as a white, off-white, or beige crystalline powder.[30] It exhibits poor solubility in water but is soluble in organic solvents such as DMSO and ethanol.[33]

3.2 Mechanism of Action

Olaparib's therapeutic effect is rooted in its dual function as a catalytic inhibitor of PARP enzymes and as an agent that "traps" these enzymes on DNA, a combination that proves synthetically lethal to cancer cells with compromised DNA repair capabilities.

• PARP Inhibition: Olaparib is a potent, competitive inhibitor of PARP enzymes, with the highest affinity for PARP1 and PARP2 (IC50​ values of 5 nM and 1 nM, respectively) and a lesser effect on PARP3 and tankyrase-1.[1] It functions by mimicking the endogenous substrate NAD+ and binding to its catalytic site, thereby preventing the synthesis of poly(ADP-ribose) (PAR) chains.[1] This PARylation process is a critical signaling event in the recruitment of repair factors to sites of DNA damage, particularly SSBs, as part of the BER pathway.[1] By blocking PARP's catalytic activity, Olaparib prevents the efficient repair of these SSBs.[21]
• Induction of Synthetic Lethality: The accumulation of unrepaired SSBs is the initiating event in the synthetic lethality cascade. During DNA replication, when replication forks encounter these unrepaired SSBs, the forks can stall and collapse, leading to the formation of highly cytotoxic DSBs.[20]
• In healthy, HR-proficient cells, these DSBs are efficiently and accurately repaired by the HR pathway, which depends on functional BRCA1 and BRCA2 proteins. These cells can therefore tolerate PARP inhibition with minimal consequence.[20]
• Conversely, in cancer cells with deleterious mutations in BRCA1, BRCA2, or other key HRR genes, the HR pathway is defective. These HR-deficient cells are unable to repair the DSBs generated by PARP inhibition.[1]
• This dual blow—the inability to repair SSBs due to PARP inhibition and the inability to repair the subsequent DSBs due to HR deficiency—results in overwhelming genomic instability, cell cycle arrest, and ultimately, apoptotic cell death.[1] This selective killing of HR-deficient cancer cells while sparing normal cells is the essence of synthetic lethality and the foundation of Olaparib's therapeutic index.
• PARP Trapping: In addition to catalytic inhibition, Olaparib exerts a more direct cytotoxic effect through a mechanism known as PARP trapping.[22] The binding of the inhibitor to the PARP enzyme can lock it onto the DNA at the site of damage, forming a stable PARP-DNA complex.[1] This complex acts as a physical impediment to DNA replication and transcription, proving to be even more toxic than an unrepaired SSB alone.[22] The potency of PARP trapping varies among different PARP inhibitors and is a significant contributor to their overall anticancer activity.[23] Olaparib is considered to have an intermediate trapping potency.[37]

3.3 Pharmacokinetics: Absorption, Distribution, Metabolism, and Elimination (ADME)

The clinical use of Olaparib is guided by its pharmacokinetic profile, which dictates its dosing schedule and potential for interactions. Its metabolism via the CYP3A4 pathway is a particularly critical factor in clinical practice.

• Absorption: Following oral administration, Olaparib is rapidly absorbed, with peak plasma concentrations (Tmax) typically reached within 1.5 to 3.0 hours.[1] The administration with a high-fat, high-calorie meal can delay the Tmax but does not significantly alter the overall extent of absorption (area under the curve, or AUC). This allows for flexible dosing with or without food.[1]
• Distribution: Olaparib has a mean apparent volume of distribution of approximately 158 L, indicating distribution into tissues.[1] In vitro, it is moderately bound to plasma proteins (approximately 82%), primarily to albumin (~56%) and to a lesser extent, alpha-1 acid glycoprotein (~29%).[1]
• Metabolism: Olaparib undergoes extensive metabolism, predominantly mediated by the cytochrome P450 isoenzyme CYP3A4 (and to a lesser extent, CYP3A5).[1] The parent drug remains the major circulating component in plasma (~70%). It is converted to numerous metabolites through reactions including oxidation, hydrolysis, and dehydrogenation, which are subsequently conjugated with glucuronide or sulfate for excretion. However, most of these metabolites are present in low concentrations (<1% of the total dose) and their pharmacodynamic activity is not well characterized.[1] The significant reliance on CYP3A4 for clearance is the primary driver of Olaparib's potential for drug-drug interactions.
• Elimination: The drug and its metabolites are eliminated from the body through both renal and fecal routes. Following a single radiolabeled dose, approximately 86% of the radioactivity was recovered within seven days, with 44% excreted in the urine and 42% in the feces.[1] A small fraction of the dose is excreted as unchanged drug in the urine (~15%) and feces (~6%), confirming that metabolism is the main elimination pathway.[1] The mean terminal elimination half-life is approximately 15 hours in cancer patients, supporting a twice-daily dosing regimen.[1]

Table 1: Key Physicochemical and Pharmacokinetic Properties of Olaparib

Property	Value / Description	Source(s)
DrugBank ID	DB09074	1
CAS Number	763113-22-0	1
IUPAC Name	4-[[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one	29
Molecular Formula	C24​H23​FN4​O3​	1
Average Molecular Weight	434.46 g/mol	1
Appearance	White to off-white solid powder	30
Drug Class	Poly(ADP-ribose) Polymerase (PARP) Inhibitor	1
Mechanism of Action	Inhibition of PARP1, PARP2, and PARP3, leading to synthetic lethality in HRR-deficient cells	1
Time to Peak (Tmax)	1.5 - 3.0 hours	1
Protein Binding	~82%	1
Metabolism Pathway	Primarily via Cytochrome P450 3A4/5 (CYP3A4/5)	1
Elimination Half-Life	~15 hours	1
Route of Elimination	~44% in urine, ~42% in feces (primarily as metabolites)	1

IV. Clinical Efficacy in Approved Indications

The clinical utility of Olaparib has been established through a series of landmark Phase III trials across multiple cancer types. These studies have not only secured regulatory approvals but have also redefined treatment paradigms by demonstrating substantial benefits in biomarker-selected patient populations.

4.1 Ovarian, Fallopian Tube, and Primary Peritoneal Cancer

Olaparib has its most extensive evidence base in ovarian cancer, where it has been approved in various settings, from first-line maintenance to the treatment of recurrent disease. The magnitude of its benefit is consistently greatest in patients with tumors harboring BRCA1/2 mutations or other evidence of homologous recombination deficiency (HRD).

4.1.1 First-Line Maintenance Monotherapy in BRCA-mutated Advanced Ovarian Cancer (SOLO-1 Trial)

The SOLO-1 trial was a practice-changing study that established Olaparib as a standard of care for first-line maintenance therapy in women with newly diagnosed, advanced BRCA-mutated ovarian cancer.

• Trial Design: SOLO-1 was a Phase III, randomized, double-blind, placebo-controlled trial. It enrolled 391 patients with newly diagnosed, advanced (FIGO Stage III-IV), high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer with a deleterious germline or somatic BRCA1/2 mutation (BRCAm). Patients had to be in a complete or partial response following first-line platinum-based chemotherapy. They were randomized 2:1 to receive Olaparib tablets (300 mg twice daily) or placebo for up to two years, or until disease progression.[41]
• Progression-Free Survival (PFS): The primary endpoint was investigator-assessed PFS. At the primary analysis, with a median follow-up of 41 months, Olaparib demonstrated an unprecedented benefit, reducing the risk of disease progression or death by 70% compared to placebo. The median PFS was not reached in the Olaparib arm, versus 13.8 months in the placebo arm (Hazard Ratio 0.30; 95% Confidence Interval [CI], 0.23–0.41; p<0.0001).[4] At 36 months, 60.4% of patients on Olaparib remained progression-free, compared to just 26.9% on placebo.[4]
• Long-Term Follow-up: The remarkable PFS benefit was sustained over long-term follow-up.
• 5-Year Follow-up: An updated analysis showed a median PFS of 56.0 months for Olaparib versus 13.8 months for placebo (HR 0.33; 95% CI, 0.25–0.43). At the 5-year mark, 48.3% of patients in the Olaparib arm were still progression-free, compared to 20.5% in the placebo arm, demonstrating a durable, long-term benefit extending well beyond the 2-year treatment period.[44]
• 7-Year Follow-up (Overall Survival): A descriptive analysis of OS after a median follow-up of over 7 years showed a clinically meaningful improvement. The median OS was not reached for Olaparib versus 75.2 months for placebo (HR 0.55; 95% CI, 0.40–0.76). At 7 years, 67.0% of patients who received Olaparib were alive, compared to 46.5% of those who received placebo.[41] This survival advantage is particularly noteworthy given that 44.3% of patients in the placebo group received a subsequent PARP inhibitor after progression, which would be expected to dilute the OS difference between the arms.[49] While the result did not meet the stringent prespecified threshold for statistical significance ( p=0.0004 vs. required p<0.0001), the magnitude of the benefit strongly supports the use of maintenance Olaparib to achieve long-term remission in this population.[41]

4.1.2 First-Line Maintenance in Combination with Bevacizumab in HRD-Positive Advanced Ovarian Cancer (PAOLA-1 Trial)

The PAOLA-1 trial investigated whether adding Olaparib to the standard-of-care maintenance anti-angiogenic agent, bevacizumab, could improve outcomes.

• Trial Design: PAOLA-1 was a Phase III, randomized, double-blind trial that enrolled 806 patients with newly diagnosed advanced high-grade ovarian cancer who were in response to first-line platinum-based chemotherapy plus bevacizumab. Patients were randomized 2:1 to receive Olaparib (300 mg twice daily) plus bevacizumab or placebo plus bevacizumab as maintenance therapy.[6] The trial included patients regardless of their BRCA status.
• Progression-Free Survival (PFS):
• HRD-Positive Subgroup: The primary analysis revealed that the benefit of adding Olaparib was almost exclusively confined to patients with HRD-positive tumors (defined as having a BRCAm and/or a high genomic instability score). In this subgroup (n=387), maintenance with Olaparib plus bevacizumab resulted in a median PFS of 37.2 months, compared to 17.7 months for placebo plus bevacizumab (HR 0.33; 95% CI, 0.25–0.45).[6] This represented a 67% reduction in the risk of progression or death.[53]
• Overall Population: In the intention-to-treat (ITT) population, the combination improved median PFS to 22.1 months versus 16.6 months for bevacizumab alone (HR 0.59).[6]
• HRD-Negative Subgroup: In contrast, there was no meaningful benefit observed in the HRD-negative subgroup (HR ~1.00), clearly demonstrating that HRD status is the key predictive biomarker for this combination's efficacy.[50]
• Overall Survival (OS): A 5-year follow-up analysis showed a clinically meaningful OS benefit in the HRD-positive subgroup. The combination of Olaparib and bevacizumab reduced the risk of death by 38% compared to bevacizumab alone (HR 0.62; 95% CI, 0.45–0.85). The median OS was 75.2 months versus 57.3 months, respectively.[52] At five years, 65.5% of patients in the combination arm were alive versus 48.4% in the control arm.[54]

4.1.3 Maintenance in Recurrent Ovarian Cancer (SOLO-2 and Study 19 Trials)

Before its success in the first-line setting, Olaparib was established as an effective maintenance therapy for patients with recurrent ovarian cancer that remains sensitive to platinum-based chemotherapy.

• SOLO-2 Trial (gBRCAm Patients): This Phase III trial randomized 295 patients with platinum-sensitive, relapsed ovarian cancer and a germline BRCA mutation (gBRCAm) to receive maintenance Olaparib tablets (300 mg twice daily) or placebo.[5]
• PFS: Olaparib provided a significant PFS benefit. Investigator-assessed median PFS was 19.1 months for Olaparib versus 5.5 months for placebo (HR 0.30; 95% CI, 0.22–0.41; p<0.0001).[5] A blinded independent central review (BICR) showed an even greater separation, with a median PFS of 30.2 months versus 5.5 months (HR 0.25).[5]
• OS: The final OS analysis, with a median follow-up of over 65 months, showed a median OS of 51.7 months with Olaparib versus 38.8 months with placebo (HR 0.74; 95% CI, 0.54–1.00; p=0.054).[56] This 12.9-month improvement in median survival, while narrowly missing statistical significance, is considered highly clinically meaningful, particularly as 38% of patients in the placebo arm crossed over to receive a PARP inhibitor upon progression.[56]
• Study 19 (All-Comers): This earlier Phase II trial randomized 265 patients with platinum-sensitive recurrent ovarian cancer, regardless of BRCA status, to Olaparib capsules (400 mg twice daily) or placebo.[3]
• PFS: The trial met its primary endpoint, showing a significant improvement in PFS for Olaparib (8.4 months vs. 4.8 months; HR 0.35).[3] The benefit was most pronounced in the BRCAm subgroup (11.2 months vs. 4.3 months; HR 0.18).[3] The results from this trial initially supported the approval of Olaparib for maintenance therapy in all patients with recurrent platinum-sensitive disease.[60] However, based on later class-effect data suggesting a potential lack of OS benefit or even detriment in non- BRCAm patients, the FDA has since restricted this indication to only patients with BRCA mutations.[63]

Table 2: Summary of Pivotal Phase III Trials for Olaparib in Ovarian Cancer

Trial	Patient Population	Treatment Arms	Primary Endpoint	Median PFS (Drug vs. Control)	PFS HR (95% CI; p-value)	Median OS (Drug vs. Control)	OS HR (95% CI; p-value)	Source(s)
SOLO-1	1L Maintenance, BRCAm	Olaparib vs. Placebo	PFS	56.0 vs. 13.8 mos	0.33 (0.25–0.43)	Not Reached vs. 75.2 mos	0.55 (0.40–0.76); p=0.0004	41
PAOLA-1	1L Maintenance, HRD-positive	Olaparib+Bev vs. Placebo+Bev	PFS (ITT)	37.2 vs. 17.7 mos	0.33 (0.25–0.45)	75.2 vs. 57.3 mos	0.62 (0.45–0.85)	6
SOLO-2	Recurrent Maintenance, gBRCAm	Olaparib vs. Placebo	PFS	19.1 vs. 5.5 mos	0.30 (0.22–0.41); p<0.0001	51.7 vs. 38.8 mos	0.74 (0.54–1.00); p=0.054	5

1L = First-Line; Bev = Bevacizumab; PFS = Progression-Free Survival; OS = Overall Survival; HR = Hazard Ratio. OS data for SOLO-1 and PAOLA-1 are from long-term follow-up analyses.

4.2 Breast Cancer

Olaparib became the first PARP inhibitor approved for breast cancer, establishing a new standard of care for patients with germline BRCA mutations in both the metastatic and, more recently, the early-stage adjuvant settings.

4.2.1 Adjuvant Treatment of gBRCAm, HER2-Negative, High-Risk Early Breast Cancer (OlympiA Trial)

The OlympiA trial evaluated the role of Olaparib in preventing recurrence in patients with high-risk early breast cancer.

• Trial Design: This was a large Phase III, randomized, double-blind, placebo-controlled trial that enrolled 1,836 patients with high-risk, HER2-negative early breast cancer and a germline BRCA1/2 mutation. After completing standard local treatments and (neo)adjuvant chemotherapy, patients were randomized 1:1 to receive one year of adjuvant Olaparib (300 mg twice daily) or placebo.[64]
• Invasive Disease-Free Survival (IDFS): The trial met its primary endpoint of IDFS.
• Primary Analysis (2.5-year follow-up): Olaparib significantly reduced the risk of invasive disease recurrence, second cancers, or death by 42% compared to placebo (HR 0.58; 99.5% CI, 0.41–0.82; p<0.0001). The 3-year IDFS rate was 85.9% for Olaparib versus 77.1% for placebo.[66]
• 6-Year Follow-up: The benefit was sustained and matured over time. At a median follow-up of 6.1 years, Olaparib reduced the risk of an IDFS event by 35% (HR 0.65; 95% CI, 0.53–0.78). The 6-year IDFS rate was 79.6% with Olaparib versus 70.3% with placebo, an absolute difference of 9.4%.[7]
• Overall Survival (OS): Critically, the improvement in IDFS translated into a statistically significant OS benefit.
• 3.5-Year Follow-up: Olaparib reduced the risk of death by 32% (HR 0.68; 98.5% CI, 0.47–0.97; p=0.009).[10]
• 6-Year Follow-up: The OS benefit was maintained, with a 28% reduction in the risk of death (HR 0.72; 95% CI, 0.56–0.93). The 6-year OS rate was 87.5% for the Olaparib group versus 83.2% for the placebo group.[7] This finding is of paramount importance, as demonstrating an OS benefit in the adjuvant setting is the ultimate goal of such therapy.

4.2.2 Treatment of gBRCAm, HER2-Negative Metastatic Breast Cancer (OlympiAD Trial)

The OlympiAD trial was the first to establish the efficacy of a PARP inhibitor over standard chemotherapy in metastatic breast cancer.

• Trial Design: This Phase III, open-label, randomized trial compared Olaparib monotherapy (300 mg twice daily) to physician's choice of standard single-agent chemotherapy (capecitabine, eribulin, or vinorelbine) in 302 patients with germline BRCA-mutated, HER2-negative metastatic breast cancer.[26]
• Progression-Free Survival (PFS): Olaparib met its primary endpoint, significantly prolonging PFS compared to chemotherapy. The median PFS was 7.0 months with Olaparib versus 4.2 months with chemotherapy (HR 0.58; 95% CI, 0.43–0.80; p=0.0009).[26]
• Objective Response Rate (ORR): The ORR was more than double in the Olaparib arm compared to the chemotherapy arm (52% vs. 23%).[26] These results led to Olaparib becoming the first PARP inhibitor approved for breast cancer, providing a targeted, oral alternative to intravenous chemotherapy for this patient population.[26]

Table 3: Summary of Pivotal Phase III Trials for Olaparib in Breast Cancer

Trial	Patient Population	Treatment Arms	Primary Endpoint	IDFS/PFS Result (HR; 95% CI; p-value)	OS Result (HR; 95% CI; p-value)	Source(s)
OlympiA	Adjuvant, High-Risk Early Breast Cancer, gBRCAm, HER2-	Olaparib vs. Placebo (1 year)	IDFS	0.65 (0.53–0.78)	0.72 (0.56–0.93)	7
OlympiAD	Metastatic Breast Cancer, gBRCAm, HER2-	Olaparib vs. Chemotherapy	PFS	0.58 (0.43–0.80); p=0.0009	Final analysis showed no significant difference	26

IDFS = Invasive Disease-Free Survival; PFS = Progression-Free Survival; OS = Overall Survival; HR = Hazard Ratio.

4.3 Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Olaparib was the first PARP inhibitor to demonstrate a survival benefit in a biomarker-selected population of men with mCRPC, a disease that remains challenging to treat after progression on androgen receptor-axis-targeted (ARAT) therapies.

4.3.1 Monotherapy in HRR-Mutated mCRPC (PROfound Trial)

The PROfound trial was a landmark study that validated the use of PARP inhibition in prostate cancer.

• Trial Design: This was a Phase III, randomized, open-label trial that enrolled men with mCRPC and a qualifying mutation in one of 15 prespecified HRR genes, whose disease had progressed on a prior new hormonal agent (NHA) like enzalutamide or abiraterone. Patients were randomized 2:1 to receive Olaparib or the physician's choice of the alternative NHA. The trial was designed with two primary cohorts: Cohort A (patients with BRCA1, BRCA2, or ATM mutations) and Cohort B (patients with mutations in any of the other 12 HRR genes).[8]
• Radiographic Progression-Free Survival (rPFS): The primary endpoint was rPFS in Cohort A.
• Cohort A: Olaparib demonstrated a significant improvement in rPFS, with a median of 7.4 months versus 3.6 months for the control arm (HR 0.34; 95% CI, 0.25–0.47; p<0.001).[72]
• BRCA-only Subgroup: The benefit was most profound in the subgroup of patients with BRCA1/2 alterations, where Olaparib reduced the risk of progression or death by 78% (median rPFS 9.8 months vs. 3.0 months; HR 0.22; 95% CI, 0.15–0.32).[8]
• Overall Survival (OS): OS was a key secondary endpoint.
• Cohort A: Olaparib significantly improved OS, with a median of 19.1 months versus 14.7 months for the control arm (HR 0.69; 95% CI, 0.50–0.97; p=0.02).[73]
• BRCA-only Subgroup: The OS benefit was also most pronounced in the BRCA subgroup (median OS 20.1 months vs. 14.4 months; HR 0.63; 95% CI, 0.42–0.95).[8] This was a critical finding, as Olaparib became the first PARP inhibitor to show an OS benefit over an active NHA control in a biomarker-selected mCRPC population.[77]

4.3.2 Combination Therapy with Abiraterone (PROpel Trial)

The PROpel trial explored moving Olaparib into the first-line mCRPC setting, in combination with the standard-of-care NHA, abiraterone.

• Trial Design: This was a Phase III, randomized, double-blind trial of Olaparib plus abiraterone versus placebo plus abiraterone in 796 patients with first-line mCRPC, irrespective of HRR mutation status.[78]
• Radiographic Progression-Free Survival (rPFS): The trial met its primary endpoint in the ITT population. The combination of Olaparib and abiraterone significantly improved rPFS compared to abiraterone alone (median 24.8 months vs. 16.6 months; HR 0.66; p<0.0001).[79]
• Subgroup Analyses and Regulatory Divergence: While the trial was positive in the overall population, an exploratory subgroup analysis revealed that the benefit was overwhelmingly driven by the patients with BRCA mutations (rPFS HR 0.24; OS HR 0.30).[78] The benefit in the non- BRCAm population was less clear. This led to a notable divergence in regulatory decisions:
• The EMA approved the combination for the broad population of men with mCRPC in whom chemotherapy is not clinically indicated, regardless of biomarker status.[81]
• The FDA, in contrast, took a more restrictive approach, granting approval only for the subgroup with a clear and substantial benefit: patients with deleterious or suspected deleterious BRCA-mutated mCRPC.[78] This highlights different regulatory philosophies regarding the interpretation of subgroup analyses within an ITT-positive trial.

4.4 Metastatic Pancreatic Adenocarcinoma

Olaparib is the first targeted therapy to show a benefit in a biomarker-selected population of patients with pancreatic cancer, a disease with notoriously poor outcomes.

4.4.1 First-Line Maintenance in gBRCAm Disease (POLO Trial)

The POLO trial established maintenance Olaparib as a new standard of care for a select group of pancreatic cancer patients.

• Trial Design: This was a Phase III, randomized, double-blind, placebo-controlled trial that enrolled 154 patients with a germline BRCA mutation and metastatic pancreatic cancer whose disease had not progressed after at least 16 weeks of first-line platinum-based chemotherapy.[9] Patients were randomized 3:2 to receive maintenance Olaparib or placebo.
• Progression-Free Survival (PFS): Olaparib met its primary endpoint, significantly improving PFS. Patients receiving maintenance Olaparib had a median PFS of 7.4 months, nearly double the 3.8 months seen in the placebo group (HR 0.53; 95% CI, 0.35–0.82; p=0.004).[9] At 2 years, 22.1% of patients on Olaparib were progression-free compared to 9.6% on placebo.[9]
• Overall Survival (OS): There was no statistically significant difference in OS between the two arms in the final analysis (median OS 18.9 months for Olaparib vs. 18.1 months for placebo).[9] This lack of OS benefit is likely influenced by the aggressive nature of the disease and the impact of subsequent therapies after progression. Nonetheless, the substantial PFS benefit established a new treatment option for this patient population.

Table 4: Summary of Pivotal Phase III Trials for Olaparib in Prostate and Pancreatic Cancer

Trial	Cancer Type	Patient Population	Treatment Arms	Primary Endpoint	rPFS/PFS Result (HR; 95% CI; p-value)	OS Result (HR; 95% CI; p-value)	Source(s)
PROfound	mCRPC	HRR-mutated (Cohort A: BRCA/ATM), post-NHA	Olaparib vs. Enzalutamide or Abiraterone	rPFS (Cohort A)	0.34 (0.25–0.47); p<0.001	0.69 (0.50–0.97); p=0.02	8
PROpel	mCRPC	1L mCRPC, ITT	Olaparib+Abi vs. Placebo+Abi	rPFS	0.66 (0.54–0.81); p<0.0001	0.83 (0.66-1.03); p=0.11 (immature)	78
POLO	Pancreatic	1L Maintenance, gBRCAm	Olaparib vs. Placebo	PFS	0.53 (0.35–0.82); p=0.004	0.91 (0.56-1.46); NS	9

mCRPC = Metastatic Castration-Resistant Prostate Cancer; NHA = New Hormonal Agent; Abi = Abiraterone; ITT = Intent-to-Treat; 1L = First-Line; NS = Not Significant.

V. Safety Profile and Tolerability

The clinical use of Olaparib requires a thorough understanding of its safety profile. While generally manageable, the drug is associated with a range of adverse reactions, including common, low-grade toxicities and rare but serious events that demand vigilant monitoring and prompt intervention.

5.1 Common and Serious Adverse Reactions

The safety profile of Olaparib varies slightly depending on the indication and whether it is used as a monotherapy or in combination with other anticancer agents.

• Monotherapy Profile: Across multiple trials in ovarian, breast, and prostate cancer, the most frequently reported adverse reactions (ARs) are gastrointestinal and constitutional symptoms.
• Common ARs (≥20%): Nausea, fatigue (including asthenia), anemia, vomiting, and diarrhea are consistently the most common ARs. Other frequent events include decreased appetite, headache, dysgeusia (taste changes), and cough.[2]
• Laboratory Abnormalities (≥25%): The most common laboratory findings are hematological, including a decrease in hemoglobin, an increase in mean corpuscular volume (MCV), and decreases in absolute lymphocyte and leukocyte counts.[85] An increase in serum creatinine is also frequently observed.[86]
• Most of these ARs are of Grade 1 or 2 severity and tend to occur early in the course of treatment, typically within the first one to three months, and are often manageable with supportive care or dose modifications.[88]
• Combination Therapy Profile:
• With Bevacizumab (PAOLA-1): When combined with bevacizumab, the AR profile reflects toxicities from both drugs. In addition to the common Olaparib-related ARs, there is a notable incidence of hypertension (46%), a known toxicity of bevacizumab. The rates of anemia (41% vs. 10%) and lymphopenia (24% vs. 9%) are substantially higher with the combination compared to bevacizumab plus placebo.[2]
• With Abiraterone (PROpel): In combination with abiraterone and prednisone for mCRPC, anemia is the most prominent AR, affecting 48% of patients. Fatigue (38%), nausea (30%), and diarrhea (19%) are also very common.[2]

5.2 Warnings, Precautions, and Contraindications

Regulatory agencies have highlighted several serious risks associated with Olaparib that require specific precautions.

• Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): This is the most severe warning associated with Olaparib.
• Incidence and Outcome: MDS/AML has occurred in approximately 1.5% of patients treated with Olaparib monotherapy in clinical trials, and the majority of these events have had a fatal outcome.[12] The risk may be higher in heavily pre-treated populations; for instance, the SOLO-2 trial reported an incidence of 8% in the Olaparib arm versus 4% in the placebo arm after long-term follow-up.[91]
• Risk Factors: All patients who developed MDS/AML had received prior chemotherapy with platinum agents or other DNA-damaging agents, and some had a history of prior malignancies or bone marrow dysplasia.[77]
• Monitoring and Management: It is imperative that patients do not start Olaparib until they have recovered from hematological toxicity caused by previous chemotherapy (to Grade 1 or less). A complete blood count must be monitored at baseline and then monthly. If prolonged, severe hematological toxicity occurs, Olaparib should be interrupted, and the patient referred to a hematologist for investigation, including bone marrow analysis and cytogenetics. If MDS/AML is confirmed, Olaparib must be permanently discontinued.[12]
• Pneumonitis: Though rare (occurring in <1% of patients), pneumonitis can be fatal.[13] Patients presenting with new or worsening respiratory symptoms such as dyspnea, cough, or fever should have Olaparib treatment interrupted pending investigation. If pneumonitis is confirmed, the drug should be permanently discontinued.[85]
• Venous Thromboembolism (VTE): This risk, which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is particularly pronounced in the mCRPC patient population. In the PROpel trial, VTE occurred in 8% of patients receiving Olaparib plus abiraterone.[13] Patients should be monitored for signs and symptoms of VTE and managed with appropriate medical intervention, including anticoagulation as indicated.[12]
• Embryo-Fetal Toxicity: Olaparib is teratogenic and can cause fetal harm based on its mechanism of action and animal studies.[85] Females of reproductive potential must use effective contraception during treatment and for 6 months after the final dose. Male patients with female partners of reproductive potential must use effective contraception during treatment and for 3 months following the last dose, and are advised not to donate sperm during this period.[12]
• Contraindications: The U.S. FDA label for Lynparza lists no absolute contraindications.[95] The EMA Summary of Product Characteristics (SmPC) lists hypersensitivity to the active substance or excipients and breastfeeding as contraindications.[96]

5.3 Management of Adverse Reactions

Proactive management of ARs is key to maintaining patients on therapy. The primary strategies are supportive care, dose interruption, and dose reduction.

• Dose Modifications: The recommended dose of 300 mg twice daily can be reduced first to 250 mg twice daily, and then to a final dose of 200 mg twice daily if necessary.[68] Dose interruptions are also frequently used to allow for recovery from acute toxicities.[88]
• Impact on Efficacy: A critical finding from an ancillary analysis of the SOLO-2 trial demonstrated that these dose reductions and interruptions, when implemented to manage ARs, did not negatively impact PFS or OS outcomes.[99] This provides strong evidence to support proactive toxicity management, assuring clinicians and patients that prioritizing safety and tolerability does not compromise the drug's efficacy. Anemia was the most common cause for dose modification in this study.[99] This finding empowers clinicians to adjust dosing to maintain patient quality of life and treatment adherence without the concern of reducing the therapeutic benefit.

Table 5: Incidence of Common (≥10%) and Grade ≥3 Adverse Reactions with Olaparib

Adverse Reaction	Monotherapy (SOLO-1)†	Combination w/ Bevacizumab (PAOLA-1)‡	Combination w/ Abiraterone (PROpel)§
	All Grades (%)	Grade ≥3 (%)	All Grades (%)
Nausea	77	3	53
Fatigue/Asthenia	67	7	53
Anemia	38	22	41
Vomiting	40	2	22
Diarrhea	37	2	18
Decreased Appetite	N/A (<20%)	N/A	N/A (<10%)
Neutropenia	23	9	18
Lymphopenia	N/A (<10%)	N/A	24
Leukopenia	N/A (<10%)	N/A	18
Hypertension	N/A (<10%)	N/A	46
Venous Thromboembolism	<1	<1	5

Data compiled from Prescribing Information and trial publications. Frequencies may vary slightly between sources. N/A indicates the reaction did not meet the reporting threshold for that trial's summary.

† Source: 2

‡ Source: 2

§ Source: 2

VI. Dosing, Administration, and Drug Interactions

Correct dosing and administration of Olaparib, including necessary adjustments for patient-specific factors and concomitant medications, are crucial for maximizing efficacy while ensuring patient safety.

6.1 Recommended Dosing and Administration

• Standard Recommended Dose: The standard dose of Olaparib is 300 mg, taken orally twice daily, for a total daily dose of 600 mg.[86] Doses should be taken approximately 12 hours apart and can be administered with or without food.[92]
• Available Formulations: Olaparib is supplied as film-coated tablets in two strengths: 150 mg (green, oval, debossed "OP150") and 100 mg (yellow, oval, debossed "OP100").[86] The 100 mg tablet is specifically available to facilitate dose reductions.[86]
• Administration Instructions: Tablets must be swallowed whole and should not be chewed, crushed, dissolved, or divided.[98] If a dose is missed, the patient should skip that dose and take the next dose at its regularly scheduled time.[94]
• Formulation Non-Interchangeability: It is critical to note that the currently available tablet formulations (100 mg, 150 mg) are not bioequivalent to the original 50 mg capsule formulation on a milligram-to-milligram basis. The capsules have been discontinued in the U.S. and should not be substituted for tablets.[60]

6.2 Dose Modifications

Dose adjustments are recommended to manage toxicity and in specific patient populations.

• For Adverse Reactions: To manage significant ARs, treatment interruption should be considered first. If the toxicity does not resolve or recurs, dose reduction is recommended. The first dose reduction is to 250 mg twice daily (total 500 mg/day), achieved by taking one 150 mg and one 100 mg tablet per dose. If a further reduction is required, the dose can be lowered to 200 mg twice daily (total 400 mg/day), using two 100 mg tablets per dose.[68]
• For Renal Impairment:
• Mild Impairment (CrCl 51-80 mL/min): No dose adjustment is necessary.[98]
• Moderate Impairment (CrCl 31-50 mL/min): The recommended dose is reduced to 200 mg twice daily (total 400 mg/day).[98]
• Severe Impairment (CrCl≤30 mL/min) or End-Stage Renal Disease: Olaparib has not been studied in this population and its use is not recommended.[104]
• For Hepatic Impairment:
• Mild to Moderate Impairment (Child-Pugh Class A and B): No starting dose adjustment is required.[39]
• Severe Impairment (Child-Pugh Class C): Olaparib has not been studied in this population and its use is not recommended.[39]

6.3 Significant Drug-Drug and Food Interactions

Olaparib's metabolism via CYP3A4 makes it highly susceptible to clinically significant drug-drug interactions (DDIs).

• CYP3A Inhibitors: Concomitant use with strong or moderate inhibitors of CYP3A can significantly increase Olaparib plasma concentrations, thereby increasing the risk of toxicity. This combination should be avoided if possible.[13]
• Strong CYP3A Inhibitors (e.g., itraconazole, ketoconazole, clarithromycin, ritonavir): If co-administration is unavoidable, the Olaparib dose must be reduced to 100 mg twice daily.[13]
• Moderate CYP3A Inhibitors (e.g., fluconazole, diltiazem, erythromycin, verapamil): If co-administration is unavoidable, the Olaparib dose must be reduced to 150 mg twice daily.[13]
• CYP3A Inducers: Concomitant use with strong or moderate inducers of CYP3A can significantly decrease Olaparib plasma concentrations, potentially leading to a loss of efficacy. This combination should be avoided.[13]
• Examples of strong/moderate inducers include rifampin, carbamazepine, phenytoin, phenobarbital, and the herbal supplement St. John's Wort.[16] A study with rifampin showed an 87% reduction in Olaparib AUC.[15]
• Food Interactions: Patients must be instructed to avoid consuming grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during treatment. These products are known inhibitors of CYP3A and can increase Olaparib plasma concentrations, similar to interacting drugs.[12]

Table 6: Recommended Dose Adjustments for Olaparib

Condition	Recommended Olaparib Dose	Total Daily Dose	Source(s)
Standard Dose	300 mg twice daily	600 mg	92
First Dose Reduction (for Adverse Reactions)	250 mg twice daily	500 mg	97
Second Dose Reduction (for Adverse Reactions)	200 mg twice daily	400 mg	97
Moderate Renal Impairment (CrCl 31-50 mL/min)	200 mg twice daily	400 mg	98
Concomitant Strong CYP3A Inhibitor	100 mg twice daily	200 mg	13
Concomitant Moderate CYP3A Inhibitor	150 mg twice daily	300 mg	13

VII. Regulatory Landscape and Companion Diagnostics

The regulatory journey of Olaparib is a compelling narrative of how a targeted therapy evolves from a niche, late-line treatment to a cornerstone of care across multiple indications and earlier lines of therapy. This evolution has been closely tied to the parallel development of companion diagnostics, cementing Olaparib's role in the era of precision oncology.

• Regulatory Approval History: Olaparib's approvals by the U.S. FDA and the EMA have expanded significantly since its debut.
• 2014: Initial accelerated approval by the FDA and conditional marketing authorisation by the EMA for heavily pre-treated patients with germline BRCA-mutated advanced ovarian cancer.[3]
• 2017-2018: A major expansion occurred with the FDA's approval of a new tablet formulation and its indication for maintenance therapy in recurrent ovarian cancer regardless of BRCA status (based on Study 19 and SOLO-2).[60] This was followed by the landmark approval for gBRCAm metastatic breast cancer (based on OlympiAD), making it the first PARP inhibitor in this setting.[3] The EMA granted a similar approval for recurrent ovarian cancer maintenance in 2018.[111]
• 2018-2020: The drug moved firmly into the first-line setting. The FDA approved Olaparib for first-line maintenance in BRCAm advanced ovarian cancer (based on SOLO-1) in December 2018.[3] This was followed by approvals for maintenance in gBRCAm metastatic pancreatic cancer (POLO trial) in December 2019 [3], and for HRR-mutated mCRPC (PROfound trial) and in combination with bevacizumab for HRD-positive ovarian cancer (PAOLA-1 trial) in May 2020.[112] The EMA followed with approvals for BRCA1/2-mutated mCRPC and the bevacizumab combination in late 2020.[115]
• 2022-2023: Olaparib's role expanded into the curative-intent setting with FDA and EMA approvals for the adjuvant treatment of high-risk, early gBRCAm breast cancer (OlympiA trial).[117] In 2023, the FDA approved the combination of Olaparib with abiraterone for BRCAm mCRPC, a more restricted label than the EMA's broader approval for this combination.[78]
• Companion Diagnostics: The use of Olaparib is inextricably linked to biomarker testing. The FDA has concurrently approved several companion diagnostics to identify eligible patients. These include:
• Myriad BRACAnalysis CDx: For detecting deleterious germline BRCA1/2 mutations in blood samples for ovarian, breast, and pancreatic cancer indications.[3]
• FoundationOne CDx: A tissue-based next-generation sequencing test to detect somatic BRCA1/2 mutations and other HRR gene alterations for ovarian and prostate cancer indications.[112]
• Myriad myChoice CDx: To determine HRD status (defined by BRCA mutation and/or genomic instability score) for selecting patients for the Olaparib plus bevacizumab combination in ovarian cancer.[112]

The requirement for an FDA-approved test for most indications underscores that Olaparib is a precision medicine whose benefit is maximized when targeted to the correct biological context.2

• Regulatory Divergence and Label Evolution: The regulatory history also reveals important nuances. The FDA's approval for first-line mCRPC in combination with abiraterone (PROpel trial) was restricted to the BRCAm subgroup, where the benefit was most profound, whereas the EMA granted a broader approval for patients in whom chemotherapy is not clinically indicated, regardless of biomarker status.[78] This divergence reflects differing regulatory philosophies on interpreting subgroup data from a trial that was positive in its overall population. Furthermore, the indication for maintenance in recurrent ovarian cancer has been subject to evolution; the FDA later restricted its use to BRCAm patients based on a class-wide review of PARP inhibitors showing a potential lack of OS benefit in the non-BRCAm population in that specific setting.[63] This demonstrates how regulatory science is dynamic, responding to the totality of emerging evidence to refine the benefit-risk assessment for specific patient groups.

Table 7: Comparison of Key FDA and EMA Approved Indications for Olaparib

Cancer Type	Indication Setting	Patient Biomarker	FDA Approval	EMA Approval	Key Trial(s)
Ovarian Cancer	1L Maintenance (Monotherapy)	BRCAm (germline or somatic)	Yes	Yes	SOLO-1
	1L Maintenance (Combination)	HRD-positive (including BRCAm)	Yes (with bevacizumab)	Yes (with bevacizumab)	PAOLA-1
	Recurrent Maintenance	BRCAm (germline or somatic)	Yes	Yes	SOLO-2, Study 19
Breast Cancer	Adjuvant	gBRCAm, HER2-negative, High-Risk	Yes	Yes	OlympiA
	Metastatic / Locally Advanced	gBRCAm, HER2-negative	Yes	Yes	OlympiAD
Prostate Cancer	mCRPC (Monotherapy, post-NHA)	HRR-mutated	Yes	BRCAm only	PROfound
	mCRPC (1L Combination)	BRCAm	Yes (with abiraterone)	Yes (with abiraterone, if chemo not indicated)	PROpel
Pancreatic Cancer	1L Maintenance	gBRCAm	Yes	Yes	POLO
Endometrial Cancer	1L Maintenance (Combination)	pMMR	No	Yes (with durvalumab)	DUO-E
1L = First-Line; L = Line; NHA = New Hormonal Agent; mCRPC = Metastatic Castration-Resistant Prostate Cancer; pMMR = Mismatch Repair Proficient. Table as of late 2024, based on provided sources. Indications may have nuances not fully captured here; refer to official prescribing information. 2

VIII. Conclusion and Future Directions

Olaparib has unequivocally transformed the treatment landscape for patients with cancers characterized by deficiencies in homologous recombination repair. As the first clinically approved PARP inhibitor, it has not only provided a powerful new therapeutic option but has also served as the clinical validation of the synthetic lethality concept, shifting the paradigm of cancer treatment toward a more precise, biomarker-driven approach. The impressive efficacy demonstrated in pivotal trials, particularly the substantial and durable progression-free survival benefits in the first-line maintenance and adjuvant settings, offers the potential for long-term remission and, for some patients, raises the possibility of a cure. The consistent benefit seen across ovarian, breast, prostate, and pancreatic cancers has firmly established Olaparib as a standard of care and has made genomic testing for BRCA and other HRR gene mutations an essential component of modern oncologic practice.

Despite its success, the story of Olaparib and PARP inhibition is still evolving. Several key challenges and future directions will shape its continued development:

• Overcoming Resistance: Acquired resistance to Olaparib is a major clinical challenge. Mechanisms of resistance are complex and can include secondary mutations that restore BRCA gene function, upregulation of drug efflux pumps, or the loss of non-homologous end-joining (NHEJ) pathways.[120] A deep understanding of these mechanisms is critical for developing the next generation of therapies. Future strategies will likely involve rational combinations designed to re-sensitize tumors to PARP inhibition or to target the resistance pathways themselves.
• Expanding to New Populations: A significant area of ongoing research is to expand the benefit of PARP inhibition beyond the canonical BRCA-mutated population. This involves two main strategies. The first is identifying new biomarkers of "BRCAness"—a phenotype of HRD that is not caused by a direct BRCA mutation but results in a similar vulnerability. The second, more innovative approach, is the concept of "pharmacologically-induced synthetic lethality".[24] This involves combining Olaparib with novel agents that can disrupt other DNA repair pathways (such as RAD51-BRCA2 disruptors) in HR-proficient tumors, thereby creating a temporary HRD-like state and rendering them sensitive to PARP inhibition. Success in this area could dramatically broaden the patient population eligible for Olaparib treatment.
• Novel Combinations: The future of Olaparib will heavily involve its use in combination regimens. The success of the PAOLA-1 (with bevacizumab) and PROpel (with abiraterone) trials has already paved the way.[6] Numerous ongoing clinical trials are exploring Olaparib in combination with other classes of drugs, most notably immunotherapy agents like PD-1/PD-L1 inhibitors (e.g., durvalumab), as well as other targeted therapies.[21] The rationale is that the DNA damage induced by Olaparib may increase tumor mutational burden and stimulate an anti-tumor immune response, creating synergy with checkpoint inhibitors.
• Long-Term Survivorship and Quality of Life: As Olaparib is used for longer durations and in earlier, curative-intent settings like adjuvant breast cancer, the focus will increasingly shift to long-term survivorship. This includes managing chronic low-grade toxicities, monitoring for rare but serious long-term risks like MDS/AML, and understanding the overall impact on patient quality of life. The reassuring finding that dose modifications do not seem to compromise efficacy will be a crucial element in optimizing long-term treatment.[99]

In conclusion, Olaparib has been a transformative force in oncology. Its journey from a basic science concept to a multi-indication cornerstone therapy is a testament to the power of precision medicine. The ongoing research into resistance mechanisms, novel combinations, and expanded indications ensures that the clinical impact of Olaparib will continue to grow, offering new hope to patients with difficult-to-treat cancers.

Works cited

1. Olaparib: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 11, 2025, https://go.drugbank.com/drugs/DB09074
2. LYNPARZA® (olaparib) PARP Inhibitor | HCP site, accessed July 11, 2025, https://www.lynparzahcp.com/
3. Olaparib - Wikipedia, accessed July 11, 2025, https://en.wikipedia.org/wiki/Olaparib
4. SOLO-1 Phase 3 Trial Demonstrates LYNPARZA® (olaparib) Maintenance Therapy Cut the Risk of Disease Progression or Death by 70 Percent in Patients with Newly-Diagnosed, Advanced BRCA-Mutated Ovarian Cancer - Merck.com, accessed July 11, 2025, https://www.merck.com/news/solo-1-phase-3-trial-demonstrates-lynparza-olaparib-maintenance-therapy-cut-the-risk-of-disease-progression-or-death-by-70-percent-in-patients-with-newly-diagnosed-advanced-brca-mutated-ovari/
5. Lynparza Phase III SOLO-2 data demonstrate progression-free ..., accessed July 11, 2025, https://www.astrazeneca.com/media-centre/press-releases/2017/lynparza-phase-iii-solo-2-data-demonstrate-progression-free-survival-benefit-in-brca-mutated-ovarian-cancer-as-maintenance-therapy-14032017.html
6. LYNPARZA® (olaparib) Phase 3 PAOLA-1 Trial Significantly ..., accessed July 11, 2025, https://www.merck.com/news/lynparza-olaparib-phase-3-paola-1-trial-significantly-increased-progression-free-survival-as-first-line-maintenance-treatment-with-bevacizumab-for-newly-diagnosed-advanced-ovarian-cancer/
7. Lynparza demonstrated clinically meaningful prolonged survival ..., accessed July 11, 2025, https://www.astrazeneca.com/media-centre/press-releases/2024/lynparza-demonstrated-clinically-meaningful-prolonged-survival-benefit-in-early-breast-cancer-in-olympia-phase-iii-trial.html
8. Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial | Journal of Clinical Oncology - ASCO Publications, accessed July 11, 2025, https://ascopubs.org/doi/10.1200/JCO.23.00339
9. PARP Inhibitors in Pancreatic Cancer: From Phase I to Plenary Session - PubMed Central, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7003614/
10. OlympiA Trial Adjuvant Olaparib Significantly Improves Overall Survival in Germline BRCA-Mutated Breast Cancer - The ASCO Post, accessed July 11, 2025, https://ascopost.com/issues/october-10-2022-supplement-breast-cancer-almanac/olympia-trial-adjuvant-olaparib-significantly-improves-overall-survival-in-germline-brca-mutated-breast-cancer/
11. Lynparza | European Medicines Agency (EMA), accessed July 11, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/lynparza
12. LYNPARZA® (olaparib) - Official Patient Website, accessed July 11, 2025, https://www.lynparza.com/
13. This label may not be the latest approved by FDA. For current ..., accessed July 11, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/208558s025lbl.pdf
14. LYNPARZA Side Effects, accessed July 11, 2025, https://www.lynparza.com/lynparza-side-effects.html
15. 206162Orig1s000 - accessdata.fda.gov, accessed July 11, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf
16. This medicinal product is subject to additional monitoring. This will allow quick identification of - Lynparza, INN-olaparib, accessed July 11, 2025, https://ec.europa.eu/health/documents/community-register/2016/20161021136129/anx_136129_en.pdf
17. Olaparib: the journey of a world-first drug | TRM CancerBRC, accessed July 11, 2025, https://www.cancerbrc.org/advance/olaparib-journey-world-first-drug
18. Our research impact: PARP inhibitors, accessed July 11, 2025, https://www.icr.ac.uk/about-us/icr-news/detail/our-research-impact-parp-inhibitors
19. Journeys of discovery: Steve Jackson and a life-saving cancer drug - University of Cambridge, accessed July 11, 2025, https://www.cam.ac.uk/stories/olaparib-cancer-drug-steve-jackson
20. Olaparib - PMC, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4693566/
21. What is the mechanism of Olaparib? - Patsnap Synapse, accessed July 11, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-olaparib
22. The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings - PMC, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5528309/
23. PARP Inhibitors: The First Synthetic Lethal Targeted Therapy - PMC - PubMed Central, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6175050/
24. Synthetic Lethality Triggered by Combining Olaparib with BRCA2–Rad51 Disruptors | ACS Chemical Biology - ACS Publications, accessed July 11, 2025, https://pubs.acs.org/doi/10.1021/acschembio.7b00707
25. A decade of clinical development of PARP inhibitors in perspective - PMC, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6771225/
26. Lynparza approved by US FDA in germline BRCA-mutated metastatic breast cancer, accessed July 11, 2025, https://www.astrazeneca.com/media-centre/press-releases/2018/lynparza-approved-by-us-fda-in-germline-brca-mutated-metastatic-breast-cancer-12012018.html
27. Olaparib (Lynparza) | Breast Cancer Now, accessed July 11, 2025, https://breastcancernow.org/about-breast-cancer/treatment/targeted-biological-therapy/olaparib-lynparza
28. Olaparib (oral route) - Mayo Clinic, accessed July 11, 2025, https://www.mayoclinic.org/drugs-supplements/olaparib-oral-route/description/drg-20127672
29. Olaparib | C24H23FN4O3 | CID 23725625 - PubChem, accessed July 11, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Olaparib
30. Olaparib | AZD-2281 | CAS#763113-22-0 | PARP inhibitor - MedKoo Biosciences, accessed July 11, 2025, https://www.medkoo.com/products/4547
31. Definition of olaparib - NCI Drug Dictionary, accessed July 11, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/olaparib
32. Olaparib | CAS 763113-22-0 | SCBT - Santa Cruz Biotechnology, accessed July 11, 2025, https://www.scbt.com/p/olaparib-763113-22-0
33. Olaparib - CAS 763113-22-0 - AdipoGen Life Sciences - PARP1 and PARP2 Inhibitor, accessed July 11, 2025, https://adipogen.com/cdx-o0144-olaparib.html
34. AZD2281 (Olaparib) - BPS Bioscience, accessed July 11, 2025, https://bpsbioscience.com/azd2281-olaparib-27003
35. Olaparib (AZD 2281, Ku-0059436, CAS Number: 763113-22-0) | Cayman Chemical, accessed July 11, 2025, https://www.caymanchem.com/product/10621/olaparib
36. Olaparib - PubMed, accessed July 11, 2025, https://pubmed.ncbi.nlm.nih.gov/30069770/
37. Pharmacokinetics and Pharmacodynamics of PARP Inhibitors in Oncology - PMC, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9734231/
38. Pharmacokinetic Interaction Between Olaparib and Regorafenib in an Animal Model - MDPI, accessed July 11, 2025, https://www.mdpi.com/1999-4923/16/12/1575
39. Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment - PMC, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7444797/
40. olaparib - Cancer Care Ontario, accessed July 11, 2025, https://www.cancercareontario.ca/en/system/files_force/olaparib.pdf?download=1
41. Overall Survival With Maintenance Olaparib at a 7-Year Follow-Up in Patients With Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The SOLO1/GOG 3004 Trial - ASCO Publications, accessed July 11, 2025, https://ascopubs.org/doi/10.1200/JCO.22.01549
42. SOLO-1 Phase III trial demonstrates Lynparza maintenance therapy cut risk of disease progression or death by 70% in patients with newly-diagnosed, advanced BRCA-mutated ovarian cancer - AstraZeneca, accessed July 11, 2025, https://www.astrazeneca.com/media-centre/press-releases/2018/solo-1-phase-III-trial-demonstrates-lynparza-maintenance-therapy-cut-risk-of-disease-progression-or-death-by-70-percent-in-patients-with-newly-diagnosed-advanced-brca-mutated-ovarian-cancer.html
43. Efficacy of Maintenance Olaparib for Patients With Newly Diagnosed Advanced Ovarian Cancer With a BRCA Mutation: Subgroup Analysis Findings From the SOLO1 Trial - PMC, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8190876/
44. SOLO-1 Trial: After 5 Years, Maintenance Olaparib Still Keeps Ovarian Cancer at Bay, accessed July 11, 2025, https://ascopost.com/issues/november-10-2020/solo-1-trial-after-5-years-maintenance-olaparib-still-keeps-ovarian-cancer-at-bay/
45. LYNPARZA SOLO-1 Trial: Efficacy in Ovarian Cancer | For HCPs, accessed July 11, 2025, https://www.lynparzahcp.com/ovarian-cancer/efficacy/solo-1.html
46. Olaparib Maintenance Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy. - Cancer Trial Results, accessed July 11, 2025, https://clin.larvol.com/trial-detail/NCT01844986
47. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial - PubMed, accessed July 11, 2025, https://pubmed.ncbi.nlm.nih.gov/34715071/
48. SOLO-1: Seven-Year Follow-up Data Confirm Maintenance Olaparib Benefit in Ovarian Cancer - ASCO Daily News, accessed July 11, 2025, https://dailynews.ascopubs.org/do/solo-1-seven-year-follow-up-data-confirm-maintenance-olaparib-benefit-ovarian-cancer
49. Overall Survival With Maintenance Olaparib at a 7-Year Follow-Up ..., accessed July 11, 2025, https://www.ascopubs.org/doi/full/10.1200/JCO.22.01549
50. PAOLA-1 Shows Benefit from Olaparib After Bevacizumab in Ovarian Cancer, accessed July 11, 2025, https://www.targetedonc.com/view/paola-1-shows-benefit-from-olaparib-after-bevacizumab-in-ovarian-cancer
51. PAOLA-1: An ENGOT/GCIG phase III trial of olaparib versus placebo combined with bevacizumab as maintenance treatment in patients with advanced ovarian cancer following first-line platinum-based chemotherapy plus bevacizumab. - ASCO, accessed July 11, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT189289
52. PAOLA-1 Phase 3 Trial – Efficacy of LYNPARZA® (olaparib) + Bevacizumab for Advanced Ovarian Cancer, accessed July 11, 2025, https://www.lynparzahcp.com/ovarian-cancer/efficacy/paola-1.html
53. Advanced Ovarian Cancer - Clinical Study Results of LYNPARZA® (olaparib), accessed July 11, 2025, https://www.lynparza.com/ovarian-cancer/results/advanced-ovarian-cancer.html
54. LYNPARZA® (olaparib) in combination with bevacizumab, and as a monotherapy, demonstrates clinically meaningful survival benefit in 1st-line advanced ovarian cancer across two Phase III trials - AstraZeneca US, accessed July 11, 2025, https://www.astrazeneca-us.com/media/press-releases/2022/lynparza-olaparib-in-combination-with-bevacizumab-and-as-a-monotherapy-demonstrates-clinically-meaningful-survival-benefit-in-1st-line-advanced-ovarian-cancer-across-two-phase-iii-trials-09092022.html
55. SOLO-2 Phase 3 Trial – Efficacy of LYNPARZA® (olaparib) for Maintenance in Recurrent Ovarian Cancer, accessed July 11, 2025, https://www.lynparzahcp.com/ovarian-cancer/efficacy/solo-2.html
56. Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial - PubMed, accessed July 11, 2025, https://pubmed.ncbi.nlm.nih.gov/33743851/
57. Olaparib - ESMO-MCBS Scorecards | ESMO, accessed July 11, 2025, https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-for-solid-tumours/esmo-mcbs-scorecards/scorecard-145-1
58. Long-Term OS Data for Olaparib Maintenance in Ovarian Cancer Show Clinically Meaningful Boost - CancerNetwork, accessed July 11, 2025, https://www.cancernetwork.com/view/long-term-os-data-for-olaparib-maintenance-in-ovarian-cancer-show-clinically-meaningful-boost
59. SOLO-2: Overall Survival Data on Olaparib for Relapsed, BRCA-Mutated Ovarian Cancer, accessed July 11, 2025, https://www.drugtopics.com/view/solo-2-overall-survival-data-olaparib-relapsed-brca-mutated-ovarian-cancer
60. FDA Expands Approval of Olaparib for Ovarian Cancer - NCI, accessed July 11, 2025, https://www.cancer.gov/news-events/cancer-currents-blog/2017/fda-olaparib-ovarian-cancer-maintenance
61. Multi-maintenance Olaparib After Disease Recurrence in Participants With Platinum Sensitive BRCAm High Grade Serous Ovarian Cancer (MOLTO) - ClinicalTrials.gov, accessed July 11, 2025, https://clinicaltrials.gov/study/NCT02855697
62. LYNPARZA® (olaparib) receives additional FDA approval in the US for ovarian cancer, accessed July 11, 2025, https://www.astrazeneca-us.com/media/press-releases/2017/lynparza-olaparib-receives-additional-fda-approval-in-the-us-for-ovarian-cancer-08172017.html
63. solo3-dhcp-final-signed.pdf - LYNPARZA® (olaparib) PARP Inhibitor, accessed July 11, 2025, https://www.lynparzahcp.com/content/dam/physician-services/us/590-lynparza-hcp-branded/hcp-global/pdf/solo3-dhcp-final-signed.pdf
64. OlympiA Trial: Long-Term Benefits of Olaparib Confirmed in High-Risk Subgroup of Breast Cancer - The ASCO Post, accessed July 11, 2025, https://ascopost.com/issues/january-25-2025/olympia-trial-long-term-benefits-of-olaparib-confirmed-in-high-risk-subgroup-of-breast-cancer/
65. PARP Inhibition Shows Long-term Survival Benefits for Patients With High-risk, BRCA-positive Breast Cancer in OlympiA Trial, accessed July 11, 2025, https://sabcs.org/Portals/0/Documents/Embargoed/GS1-09%20press%20release.pdf?ver=YIyjCwFJ6S0-oseVGQxfYA%3D%3D
66. OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER2-negative early breast cancer., accessed July 11, 2025, https://meetings.asco.org/abstracts-presentations/196707
67. LYNPARZA® (olaparib) Demonstrated Clinically Meaningful Prolonged Survival Benefit in Early Breast Cancer in OlympiA Phase 3 Trial - Merck.com, accessed July 11, 2025, https://www.merck.com/news/lynparza-olaparib-demonstrated-clinically-meaningful-prolonged-survival-benefit-in-early-breast-cancer-in-olympia-phase-3-trial/
68. Dosing & Administration – gBRCAm, HER2-Negative, Breast Cancer - LYNPARZA® (olaparib) PARP Inhibitor, accessed July 11, 2025, https://www.lynparzahcp.com/breast-cancer/dosing.html
69. Adjuvant Olaparib for Germline BRCA Carriers With HER2- Negative Early Breast Cancer: Evidence and Controversies - Oxford Academic, accessed July 11, 2025, https://academic.oup.com/oncolo/article-pdf/28/7/565/50825987/oyad123.pdf
70. ESMO-MCBS Scorecards - Olaparib, accessed July 11, 2025, https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-for-solid-tumours/esmo-mcbs-scorecards/scorecard-166-1
71. LYNPARZA® (olaparib) Phase 3 PROfound Trial in HRR Mutation-Selected Metastatic Castration-Resistant Prostate Cancer Met Primary Endpoint - Merck.com, accessed July 11, 2025, https://www.merck.com/news/lynparza-olaparib-phase-3-profound-trial-in-hrr-mutation-selected-metastatic-castration-resistant-prostate-cancer-met-primary-endpoint/
72. PROfound Trial Evaluates Olaparib in Homologous Recombination Repair Gene–Mutant Prostate Cancer - The ASCO Post, accessed July 11, 2025, https://ascopost.com/issues/september-10-2020/profound-trial-evaluates-olaparib-in-homologous-recombination-repair-gene-mutant-prostate-cancer/
73. Overall Survival Analysis in the PROfound Trial of Olaparib for Metastatic Castration-Resistant Prostate Cancer - The ASCO Post, accessed July 11, 2025, https://ascopost.com/news/september-2020/overall-survival-analysis-in-the-profound-trial-of-olaparib-for-metastatic-castration-resistant-prostate-cancer/
74. PROfound Trial Efficacy – LYNPARZA® (olaparib) for HRRm mCRPC, accessed July 11, 2025, https://www.lynparzahcp.com/prostate-cancer/efficacy/monotherapy.html
75. Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial | Journal of Clinical Oncology - ASCO Publications, accessed July 11, 2025, https://ascopubs.org/doi/abs/10.1200/JCO.23.00339
76. Olaparib for the Treatment of Patients With Metastatic Castration ..., accessed July 11, 2025, https://www.ascopubs.org/doi/full/10.1200/JCO.23.00339
77. LYNPARZA® (olaparib) Approved in the EU for Treatment of BRCA1/2-Mutated Metastatic Castration-Resistant Prostate Cancer (mCRPC) - Merck.com, accessed July 11, 2025, https://www.merck.com/news/lynparza-olaparib-approved-in-the-eu-for-treatment-of-brca1-2-mutated-metastatic-castration-resistant-prostate-cancer-mcrpc/
78. FDA Approves LYNPARZA® (olaparib) Plus Abiraterone and Prednisone or Prednisolone for Treatment of Adult Patients With BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer (mCRPC) - Merck.com, accessed July 11, 2025, https://www.merck.com/news/fda-approves-lynparza-olaparibplus-abiraterone-and-prednisone-or-prednisolone-for-treatment-of-adult-patients-with-brca-mutated-metastatic-castration-resistant-prostate-cancer-mcrpc/
79. In Brief: A New Prostate Cancer Indication for Olaparib (Lynparza) (online only), accessed July 11, 2025, https://secure.medicalletter.org/TML-article-1679g
80. Lynparza in combination with abiraterone approved in the EU as 1st-line treatment for patients with metastatic castration-resistant prostate cancer - AstraZeneca, accessed July 11, 2025, https://www.astrazeneca.com/media-centre/press-releases/2022/lynparza-approved-in-eu-for-prostate-cancer.html
81. EMA Recommends Extension of Therapeutic Indications for Olaparib to Patients with Endometrial Cancer | ESMO, accessed July 11, 2025, https://www.esmo.org/oncology-news/ema-recommends-extension-of-therapeutic-indications-for-olaparib-to-patients-with-endometrial-cancer
82. Europe broadens Lynparza use as FDA ups scrutiny of PARP drugs - BioPharma Dive, accessed July 11, 2025, https://www.biopharmadive.com/news/lynparza-eu-approval-prostate-cancer-fda-parp/639298/
83. FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer, accessed July 11, 2025, https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-abiraterone-and-prednisone-or-prednisolone-brca-mutated-metastatic-castration
84. FDA approves olaparib for gBRCAm metastatic pancreatic adenocarcinoma, accessed July 11, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-gbrcam-metastatic-pancreatic-adenocarcinoma
85. LYNPARZA® (olaparib) capsules, for oral use - accessdata.fda.gov, accessed July 11, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206162s011lbl.pdf
86. LYNPARZA® (olaparib) tablets, for oral use - accessdata.fda.gov, accessed July 11, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208558s001lbl.pdf
87. Lynparza (olaparib) CAPSULE [AstraZeneca Pharmaceuticals LP] - PI-Central, accessed July 11, 2025, https://www.azpicentral.com/pi.html?product=lynparza
88. Monotherapy – Dosing and Administration for LYNPARZA® (olaparib), accessed July 11, 2025, https://www.lynparzahcp.com/ovarian-cancer/dosing/monotherapy.html
89. Age Is a Risk Factor for Olaparib Dose Modification and Discontinuation in Patients With Ovarian Cancer, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11215453/
90. Adverse Reactions and Tolerability for LYNPARZA® (olaparib) in PAOLA-1, accessed July 11, 2025, https://www.lynparzahcp.com/ovarian-cancer/safety-tolerability/paola-1.html
91. Management Of Select Adverse Reactions – LYNPARZA® (olaparib), accessed July 11, 2025, https://www.lynparzaarguide.com/management-of-select-ars
92. Dosing & Administration Guidelines – LYNPARZA® (olaparib) for HRRm mCRPC, accessed July 11, 2025, https://www.lynparzahcp.com/prostate-cancer/dosing.html
93. What Is LYNPARZA® (olaparib)? - Lynparza.com, accessed July 11, 2025, https://www.lynparza.com/what-is-lynparza.html
94. Olaparib: MedlinePlus Drug Information, accessed July 11, 2025, https://medlineplus.gov/druginfo/meds/a614060.html
95. Patient Forms and Resources - LYNPARZA® (olaparib) PARP Inhibitor, accessed July 11, 2025, https://www.lynparzahcp.com/patient-support/forms-and-resources.html
96. lynparza-epar-product-information_en.pdf - European Medicines Agency, accessed July 11, 2025, https://www.ema.europa.eu/en/documents/product-information/lynparza-epar-product-information_en.pdf
97. Dosing & Management – LYNPARZA® (olaparib) for Metastatic Pancreatic Cancer, accessed July 11, 2025, https://www.lynparzahcp.com/pancreatic-cancer/dosing.html
98. Reference ID: 4140621 This label may not be the latest approved by FDA. For current labeling information, please visit https:// - accessdata.fda.gov, accessed July 11, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208558s000lbl.pdf
99. No Impact on Survival from Dose Reduction and Interruption for the Management of Olaparib Associated Adverse Events | ESMO, accessed July 11, 2025, https://www.esmo.org/oncology-news/no-impact-on-survival-from-dose-reduction-and-interruption-for-the-management-of-olaparib-associated-adverse-events
100. PARP dose can be safely lowered for ovarian cancer | FORCE XRAY review, accessed July 11, 2025, https://www.facingourrisk.org/XRAY/PARP-dose-reduction-for-ovarian-cancer
101. Lynparza (olaparib): Uses, Side Effects, Dosage & Reviews - GoodRx, accessed July 11, 2025, https://www.goodrx.com/lynparza/what-is
102. Olaparib tablets (Prostate) | SWAG Cancer Alliance - Quick Reference Guide - MRSA Topical Eradication, accessed July 11, 2025, https://www.swagcanceralliance.nhs.uk/wp-content/uploads/2023/07/Olaparib-prostate-v1.pdf
103. Administration of the Tablet Formulation of Olaparib in Patients with Ovarian Cancer: Practical Guidance and Expectations - PubMed Central, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6067940/
104. Lynparza (olaparib) dosing, indications, interactions, adverse effects, and more, accessed July 11, 2025, https://reference.medscape.com/drug/lynparza-olaparib-999934
105. Lynparza - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed July 11, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208558s014lbl.pdf
106. BC Cancer Protocol Summary for Treatment of Metastatic Castration- Resistant Prostate Cancer using Olaparib, accessed July 11, 2025, http://www.bccancer.bc.ca/chemotherapy-protocols-site/Documents/Genitourinary/UGUPOLAP_protocol.pdf
107. Physiologically Based Pharmacokinetic Modeling for Olaparib Dosing Recommendations: Bridging Formulations, Drug Interactions, and Patient Populations, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6585620/
108. Olaparib tablets (Breast) - Quick Reference Guide - MRSA Topical Eradication, accessed July 11, 2025, https://www.swagcanceralliance.nhs.uk/wp-content/uploads/2023/08/Olaparib-breast-v1.pdf
109. Lynparza, INN-olaparib - National Drug Information, accessed July 11, 2025, https://ndi.fda.moph.go.th/uploads/drug_doc/Olaparib_SmPC_NDI.pdf
110. LYNPARZA™ approved by the US food and drug administration for the treatment of advanced ovarian cancer in patients with germline BRCA-mutations - AstraZeneca, accessed July 11, 2025, https://www.astrazeneca.com/media-centre/press-releases/2014/lynparza-approved-us-fda-brca-mutated-ovarian-cancer-treatment-19122014.html
111. LYNPARZA® (olaparib) Tablets Receive EU Approval for the Treatment of Platinum-Sensitive Relapsed Ovarian Cancer - Merck.com, accessed July 11, 2025, https://www.merck.com/news/lynparza-olaparib-tablets-receive-eu-approval-for-the-treatment-of-platinum-sensitive-relapsed-ovarian-cancer/
112. FDA Approval Summary: Olaparib Monotherapy or in Combination with Bevacizumab for the Maintenance Treatment of Patients with Advanced Ovarian Cancer - PubMed, accessed July 11, 2025, https://pubmed.ncbi.nlm.nih.gov/33017510/
113. FDA expands approval of Lynparza for women with advanced ovarian cancer, accessed July 11, 2025, https://www.facingourrisk.org/XRAY/new-combination-therapy-approved-for-ovarian-cancer
114. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer, accessed July 11, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer
115. Lynparza approved in the EU for the treatment of BRCA-mutated metastatic castration-resistant prostate cancer - AstraZeneca, accessed July 11, 2025, https://www.astrazeneca.com/media-centre/press-releases/2020/lynparza-approved-in-the-eu-for-prostate-cancer.html
116. Lynparza scores two new EU approvals - PharmaTimes, accessed July 11, 2025, https://pharmatimes.com/news/lynparza_scores_two_new_eu_approvals_1356198/
117. Lynparza approved in the EU as adjuvant treatment for patients with germline BRCA-mutated HER2-negative high-risk early breast cancer - AstraZeneca, accessed July 11, 2025, https://www.astrazeneca.com/media-centre/press-releases/2022/lynparza-approved-in-eu-for-early-breast-cancer.html
118. FDA approves olaparib for adjuvant treatment of high-risk early breast cancer, accessed July 11, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-adjuvant-treatment-high-risk-early-breast-cancer
119. Olaparib Monograph for Professionals - Drugs.com, accessed July 11, 2025, https://www.drugs.com/monograph/olaparib.html
120. Synthetic lethality between BRCA1 deficiency and poly(ADP-ribose) polymerase inhibition is modulated by processing of endogenous oxidative DNA damage | Nucleic Acids Research | Oxford Academic, accessed July 11, 2025, https://academic.oup.com/nar/article/47/17/9132/5536981
121. Molecular Targets 2021: Examining Synthetic Lethality Beyond PARP Inhibitors, accessed July 11, 2025, https://www.aacr.org/blog/2021/12/06/molecular-targets-2021-examining-synthetic-lethality-beyond-parp-inhibitors/
122. Synthetic Lethality in Pancreatic Cancer: Discovery of a New RAD51-BRCA2 Small Molecule Disruptor That Inhibits Homologous Recombination and Synergizes with Olaparib - ACS Publications, accessed July 11, 2025, https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01526
123. Pancreatic Cancer Recruiting Phase 1 Trials for Olaparib (DB09074) | DrugBank Online, accessed July 11, 2025, https://go.drugbank.com/indications/DBCOND0028482/clinical_trials/DB09074?phase=1&status=recruiting