A Comprehensive Monograph on Talazoparib (Talzenna®): From Molecular Mechanism to Clinical Practice

I. Executive Summary

Talazoparib, marketed under the brand name Talzenna®, is a highly potent, orally bioavailable small molecule inhibitor of the poly (ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2. Its therapeutic effect is rooted in the principle of synthetic lethality, a mechanism particularly effective in tumors harboring deficiencies in the homologous recombination repair (HRR) pathway, most notably those with germline mutations in the BRCA1 or BRCA2 genes. Talazoparib is distinguished from other agents in its class by a dual mechanism of action that combines catalytic inhibition of the PARP enzyme with exceptionally potent "PARP trapping," a process that sequesters the enzyme on DNA, forming a cytotoxic complex that is profoundly disruptive to DNA replication. This high trapping efficiency is believed to be a key driver of its clinical activity.

Talazoparib has secured regulatory approval for two primary indications based on robust clinical evidence from pivotal Phase 3 trials. First, as a monotherapy for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative locally advanced or metastatic breast cancer, an approval supported by the EMBRACA trial. This study demonstrated a significant improvement in progression-free survival (PFS) for Talazoparib compared to standard chemotherapy. Second, it is approved in combination with the androgen receptor inhibitor enzalutamide for the treatment of adult patients with HRR gene-mutated metastatic castration-resistant prostate cancer (mCRPC). This indication was established by the TALAPRO-2 trial, which showed a marked improvement in radiographic progression-free survival (rPFS) and a clinically meaningful benefit in overall survival (OS).

The clinical use of Talazoparib is characterized by a well-defined and predictable safety profile. The primary dose-limiting toxicities are hematological, including high rates of anemia, neutropenia, and thrombocytopenia. These adverse events are considered on-target effects related to the drug's potent mechanism of action and are typically manageable through a structured regimen of monitoring, dose interruption, and dose reduction. This comprehensive monograph provides a detailed analysis of Talazoparib, covering its chemical and pharmaceutical properties, pharmacological profile, pivotal clinical trial data, safety and tolerability, and guidelines for its clinical application.

II. Chemical and Pharmaceutical Profile

2.1. Identification and Physicochemical Properties

Talazoparib is a small molecule drug with a complex heterocyclic structure. Its unambiguous identification is established through a series of internationally recognized names and numbers. The active pharmaceutical ingredient possesses a specific stereochemistry at two chiral centers, designated as (8S,9R), which is critical for its potent biological activity.[1] Alternative names used during its development include BMN-673, LT-673, and MDV-3800.[1] A consolidation of its key identifiers and properties is provided in Table 1.

Table 1: Physicochemical Properties of Talazoparib

Property	Value	Source(s)
Drug Name	Talazoparib	5
Brand Name	Talzenna®	1
Alternate/Code Names	BMN-673, LT-673, MDV-3800	1
Systematic (IUPAC) Name	(8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one	1
CAS Number	1207456-01-6	1
DrugBank ID	DB11760	1
Molecular Formula	C19​H14​F2​N6​O	1
Molar Mass	380.359 g·mol⁻¹	1
PubChem CID	135565082	1
UNII	9QHX048FRV	1

2.2. Chemical Synthesis Pathway

The manufacturing of Talazoparib involves a multi-step chemical synthesis designed to efficiently produce the correct and biologically active (8S,9R) enantiomer. One patented method, suitable for industrial production, avoids the use of metal catalysts and cryogenic conditions, thereby simplifying the process.[6] This pathway can be summarized in four main stages [6]:

1. Formation of a Tetrahydroisoquinoline Intermediate: The synthesis begins with the reaction of a substituted isobenzofuranone (compound of formula 14) with 4-fluorobenzaldehyde (compound of formula 15) in dioxane, catalyzed by pyridinium p-toluenesulfonate (PPTS) in the presence of magnesium sulfate (MgSO4​). The resulting imine is then reduced in situ with sodium borohydride (NaBH4​) to yield a racemic tetrahydroisoquinoline intermediate (compound 16).[6]
2. Chiral Resolution: This critical step isolates the desired stereoisomer. The racemic intermediate (compound 16) is treated with D(-)-tartaric acid in ethanol. This forms a diastereomeric salt with the desired (S,R) amine, which selectively precipitates from the solution. Subsequent treatment with a base liberates the enantiomerically pure amine intermediate (compound 17).[6] The incorporation of an efficient, early-stage chiral resolution is a key feature of this synthesis, ensuring that subsequent steps build upon the correct stereochemical framework. This approach is often more scalable and cost-effective for industrial manufacturing than late-stage separation techniques like chiral chromatography, which has also been described for Talazoparib.[6]
3. Triazole Coupling: The enantiopure amine (compound 17) is then coupled with an activated triazole derivative (compound 18). The reaction is typically carried out in an anhydrous solvent like tetrahydrofuran (THF) using a base such as sodium alcoholate to yield the penultimate intermediate (compound 13).[6]
4. Final Cyclization to form the Phthalazinone Ring: The final step involves the cyclization of the intermediate (compound 13) with hydrazine hydrate in ethanol under reflux. This reaction forms the fused phthalazinone ring system, completing the tetracyclic core of Talazoparib (compound 1).[6] The crude product is then purified via washing and recrystallization to yield the final active pharmaceutical ingredient.

2.3. Formulation and Dosage Forms

Talazoparib is formulated for oral administration as hard capsules, which allows for convenient once-daily dosing.[1] The drug is marketed under the brand name Talzenna® in a range of strengths to provide clinicians with the flexibility needed for dose adjustments in response to adverse events.[9] The availability of multiple, finely-graded capsule strengths is a direct and necessary consequence of the drug's potent, mechanism-based toxicities, particularly myelosuppression. This formulation strategy is inextricably linked to the clinical risk management plan, enabling precise dose titration to balance efficacy and tolerability for individual patients.

The available capsule strengths include 1 mg, 0.75 mg, 0.5 mg, 0.35 mg, 0.25 mg, and 0.1 mg.[10] To prevent medication errors, each strength has a distinct appearance, characterized by different colored caps and specific black ink imprints [13]:

• 1 mg: Light red cap ("Pfizer") and white body ("TLZ 1")
• 0.75 mg: Light orange cap ("Pfizer") and white body ("TLZ 0.75")
• 0.5 mg: Light pink cap ("Pfizer") and white body ("TLZ 0.5")
• 0.25 mg: Ivory cap ("Pfizer") and white body ("TLZ 0.25")

Patients are instructed to swallow the capsules whole; they must not be opened, crushed, broken, or dissolved.[8]

III. Pharmacological Profile

3.1. Mechanism of Action: Dual-Inhibition and PARP Trapping

Talazoparib is an inhibitor of the PARP family of enzymes, with high potency against PARP1 and PARP2.[3] These enzymes are central to the base excision repair (BER) pathway, a cellular mechanism responsible for repairing DNA single-strand breaks (SSBs).[1] The therapeutic strategy of Talazoparib is based on the concept of

synthetic lethality. In normal cells possessing a functional homologous recombination repair (HRR) pathway, the inhibition of PARP is generally tolerated because the HRR machinery can effectively repair the more complex double-strand breaks (DSBs) that arise from unrepaired SSBs during DNA replication.[16]

However, certain cancers, particularly those with germline mutations in BRCA1, BRCA2, or other HRR-related genes (ATM, PALB2, etc.), have a deficient HRR pathway.[16] These tumor cells become critically dependent on the PARP-mediated BER pathway for DNA repair and survival.[1] When Talazoparib inhibits PARP in these HRR-deficient cells, SSBs accumulate and are converted into DSBs during replication. Without a functional HRR pathway to repair these DSBs, the cell undergoes catastrophic genomic instability, cell cycle arrest, and ultimately, apoptosis (programmed cell death).[14]

A defining characteristic that distinguishes Talazoparib from other PARP inhibitors is its dual mechanism of action, which encompasses both catalytic inhibition and exceptionally potent PARP trapping. Beyond simply blocking the enzymatic activity of PARP, Talazoparib traps the PARP enzyme onto the DNA at the site of a break, forming a highly cytotoxic PARP-DNA complex.[1] This trapped complex acts as a physical barrier that stalls replication forks and obstructs access by other DNA repair proteins, leading to profound cellular toxicity.[2] Preclinical studies indicate that Talazoparib is the most potent PARP-trapper identified to date, with a trapping efficiency approximately 100-fold greater than that of olaparib.[1] Its half-maximal inhibitory concentration (

IC50​) for PARP1 in cell-free assays is 0.57 nM, underscoring its high potency.[3]

This extreme potency in PARP trapping can be viewed as a double-edged sword. It is the molecular foundation for Talazoparib's robust anti-tumor efficacy in susceptible cancers. At the same time, this intense, on-target mechanism is also the primary driver of its most significant dose-limiting toxicities. Rapidly proliferating cells, such as hematopoietic stem cells in the bone marrow, are highly reliant on efficient DNA replication and repair. The profound replication stress induced by Talazoparib's trapping activity leads to significant collateral damage in these healthy tissues, manifesting clinically as the myelosuppression (anemia, neutropenia, and thrombocytopenia) that characterizes its safety profile. Thus, the drug's primary adverse effects are not off-target phenomena but are a direct and predictable consequence of its powerful on-target mechanism.

3.2. Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Talazoparib is characterized by rapid oral absorption, extensive tissue distribution, minimal metabolism, and primary elimination via the kidneys as an unchanged drug. This profile directly informs its clinical dosing schedule and management guidelines. A summary of key parameters is provided in Table 2.

Table 2: Summary of Key Pharmacokinetic Parameters of Talazoparib

Parameter	Value	Source(s)
Time to Max. Concentration (Tmax​)	Median: 1-2 hours	2
Effect of High-Fat Meal	Cmax​ increases by 46%, Tmax​ delayed to 4 hours, no effect on AUC	15
Apparent Volume of Distribution (Vd​/F)	420 L	15
Plasma Protein Binding	~74% (concentration-independent)	1
Metabolism	Minimal (<30%)	1
Primary Elimination Route	Renal excretion of unchanged drug	1
Excretion	69% in urine (55% unchanged), 20% in feces (14% unchanged)	1
Terminal Half-Life (t1/2​)	90 (±58) hours	1
Apparent Oral Clearance (CL/F)	6.45 L/h	15
Time to Steady State	2-3 weeks	2

• Absorption: Following oral administration, Talazoparib is absorbed rapidly, reaching peak plasma concentrations (Cmax​) in a median time of one to two hours.[2] While a high-fat, high-calorie meal can increase the peak concentration and delay its timing, it does not alter the total drug exposure (Area Under the Curve, AUC).[15] This finding supports the clinical recommendation that Talazoparib can be administered with or without food, enhancing patient convenience.[10]
• Distribution: Talazoparib has a large apparent volume of distribution of 420 L, indicating that the drug distributes extensively from the plasma into body tissues.[15] It is moderately bound (~74%) to plasma proteins, and this binding is independent of the drug concentration.[1]
• Metabolism: A key feature of Talazoparib's profile is its minimal metabolism, with less than 30% of the drug being metabolized by the liver.[1] The minor metabolic pathways that have been identified include mono-oxidation and dehydrogenation.[15] This low reliance on hepatic metabolism, particularly cytochrome P450 (CYP) enzymes, means that Talazoparib has a low potential for clinically significant drug-drug interactions with CYP inhibitors or inducers.[24]
• Excretion: The primary pathway for eliminating Talazoparib from the body is renal excretion. Approximately 69% of an administered dose is recovered in the urine, with the majority (55% of the total dose) being the unchanged parent drug. A smaller fraction (~20%) is recovered in the feces.[1]

The pharmacokinetic properties of Talazoparib are the direct cause for its specific clinical management guidelines. The long terminal half-life of 90 hours supports a convenient once-daily dosing regimen.[1] The primary reliance on renal excretion for clearance means that patients with impaired kidney function are at risk of drug accumulation and increased toxicity. This directly explains why the prescribing information includes mandatory dose reduction guidelines for patients with moderate to severe renal impairment.[9] Conversely, the minimal hepatic metabolism explains the lack of specific dose adjustments for hepatic impairment.[25] Furthermore, this profile dictates that the most clinically relevant drug-drug interactions are not with metabolic enzyme modulators, but with inhibitors of efflux transporter proteins like P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), which can affect the drug's absorption and distribution.[26]

3.3. Pharmacodynamics

The relationship between Talazoparib exposure and its clinical effects (both efficacy and safety) has not been fully characterized.[14] However, a clear exposure-toxicity relationship has been established for its primary adverse effect. Analysis from the EMBRACA trial demonstrated that higher plasma concentrations of Talazoparib were associated with a greater incidence of Grade ≥3 anemia, confirming that this on-target toxicity is dose- and exposure-dependent.[22]

In terms of cardiac safety, dedicated studies have shown that Talazoparib, at the recommended therapeutic dose of 1 mg daily, does not cause large prolongations of the QT interval on an electrocardiogram (ECG) (i.e., >20 ms).[2] This indicates a low risk of inducing potentially fatal cardiac arrhythmias such as Torsades de Pointes, a significant safety advantage.

IV. Clinical Efficacy in Oncology

4.1. Overview of Clinical Development

The clinical development program for Talazoparib has established its efficacy in specific, biomarker-defined cancer populations. Early-phase (Phase 1) studies evaluated the safety, tolerability, and preliminary activity of Talazoparib in patients with a variety of advanced solid tumors, including breast, ovarian, pancreatic, prostate, colorectal, and non-small cell lung cancer.[29] These studies identified a promising signal in tumors with known DNA damage repair defects.

Subsequent Phase 2 trials, such as the ABRAZO study (NCT02034916), provided more robust evidence of clinical benefit in heavily pretreated patients with gBRCA-mutated advanced breast cancer.[21] The promising activity observed in these trials provided the rationale for launching two large, pivotal Phase 3 studies—EMBRACA and TALAPRO-2—which ultimately formed the basis for its regulatory approvals. Concurrently, Phase 2 trials continue to explore Talazoparib's potential in other settings, such as in combination with agents like abemaciclib and capivasertib for various breast cancer subtypes.[31]

4.2. Pivotal Trial Analysis: EMBRACA in gBRCA-Mutated Breast Cancer

The EMBRACA trial (NCT01945775) was the cornerstone study that established Talazoparib as a standard of care for patients with gBRCA-mutated advanced breast cancer.[30]

4.2.1. Study Design and Patient Population

EMBRACA was a global, multicenter, open-label, randomized Phase 3 trial that enrolled 431 patients.[21] Eligible patients had deleterious or suspected deleterious germline mutations in either the

BRCA1 or BRCA2 gene and had HER2-negative locally advanced or metastatic breast cancer.[32] The patient population was representative of this disease setting, including individuals with hormone receptor-positive (HR+) disease (54%) and triple-negative breast cancer (TNBC) (46%).[35] Patients were required to have received no more than three prior cytotoxic chemotherapy regimens for advanced disease and must have been treated with an anthracycline and/or a taxane in a prior setting, unless contraindicated.[8]

Patients were randomized in a 2:1 ratio to receive either Talazoparib (1 mg orally once daily) or the physician's choice of standard single-agent chemotherapy (PCT), which included capecitabine, eribulin, gemcitabine, or vinorelbine.[21]

4.2.2. Efficacy Outcomes: PFS, OS, and Response Rates

The EMBRACA trial successfully met its primary endpoint, demonstrating the superiority of Talazoparib over standard chemotherapy. However, the results for the key secondary endpoint of overall survival presented a more complex picture. A summary of the key efficacy outcomes is presented in Table 3.

Table 3: Summary of Efficacy Results from the EMBRACA Trial

Efficacy Endpoint	Talazoparib (n=287)	Chemotherapy (n=144)	Hazard Ratio (HR) / Odds Ratio (OR) (95% CI)	p-Value	Source(s)
Median PFS (Primary)	8.6 months	5.6 months	HR: 0.54 (0.41, 0.71)	<0.0001	30
Objective Response Rate (ORR)	62.6%	27.2%	OR: 4.99 (2.9, 8.8)	<0.0001	30
Median OS (Final)	19.3 months	19.5 months	HR: 0.848 (0.670, 1.073)	0.17	21

The primary outcome, progression-free survival (PFS) as assessed by blinded independent central review, was significantly longer in the Talazoparib arm. The median PFS was 8.6 months for patients treated with Talazoparib compared to 5.6 months for those receiving chemotherapy.[30] This corresponded to a hazard ratio (HR) of 0.54, representing a 46% reduction in the risk of disease progression or death (p<0.0001).[32] This robust PFS benefit was consistent across all key patient subgroups, including by HR status (HR+ or TNBC), type of BRCA mutation (

BRCA1 or BRCA2), and number of prior chemotherapy lines.[30] Furthermore, the objective response rate (ORR) was more than doubled with Talazoparib (62.6%) compared to chemotherapy (27.2%).[30]

In contrast to the strong PFS data, the final analysis of the key secondary endpoint, overall survival (OS), did not demonstrate a statistically significant benefit for Talazoparib. After a median follow-up of approximately 45 months in the Talazoparib arm, the median OS was 19.3 months, nearly identical to the 19.5 months observed in the chemotherapy arm (HR 0.848; p=0.17).[36] This apparent discrepancy between a large PFS benefit and no OS benefit is a classic example of how post-progression therapies can confound survival outcomes in modern oncology trials. The trial data revealed that a substantial proportion of patients in the control arm received effective subsequent treatments after their disease progressed on chemotherapy. Specifically, 32.6% of patients in the chemotherapy arm crossed over to receive a subsequent PARP inhibitor, the very class of drug being tested.[21] Additionally, high rates of subsequent platinum-based chemotherapy, which is known to be particularly effective in BRCA-mutated cancers, were used in both arms.[21] The use of these effective subsequent therapies in the control group likely "rescued" those patients, extending their survival and masking or diluting the true survival benefit of receiving Talazoparib as an earlier line of treatment. This confounding effect was acknowledged in the trial's final publications.[21] Therefore, the OS result should not be interpreted as a failure of the drug's activity but rather as an artifact of the trial's design and the evolving treatment landscape. The significant improvements in PFS and quality of life remain the primary indicators of Talazoparib's clinical value in this patient population.

4.2.3. Patient-Reported Outcomes and Quality of Life

Despite the lack of an OS benefit, Talazoparib provided a significant and meaningful improvement in patients' quality of life (QoL). Patient-reported outcome (PRO) analyses showed a statistically significant delay in the time to definitive clinically meaningful deterioration of global health status.[21] The median time to deterioration was 26.3 months for patients on Talazoparib, a stark contrast to just 6.7 months for those on chemotherapy.[35] This demonstrates that, in addition to controlling the disease for longer (PFS), Talazoparib allowed patients to maintain their overall well-being and functionality for a significantly longer period compared to standard cytotoxic treatments.

4.3. Pivotal Trial Analysis: TALAPRO-2 in HRR-Mutated Prostate Cancer

The TALAPRO-2 trial (NCT03395197) was a landmark study that established a new combination therapy standard for first-line metastatic castration-resistant prostate cancer (mCRPC) and expanded Talazoparib's indications.[17]

4.3.1. Study Design and Rationale for Combination Therapy

TALAPRO-2 was a large, Phase 3, randomized, double-blind, placebo-controlled trial that evaluated Talazoparib in combination with the standard-of-care androgen receptor pathway inhibitor (ARPI), enzalutamide.[17] The study enrolled over 1,000 men with mCRPC who had not yet received systemic treatment for their castration-resistant disease.[41] The trial was designed with two primary cohorts: an "all-comer" population (unselected for biomarker status) and a cohort of patients prospectively confirmed to have mutations in one of 12 pre-specified HRR genes (including

BRCA1/2, ATM, PALB2, and CHEK2).[17] Patients were randomized 1:1 to receive either Talazoparib (at a reduced dose of 0.5 mg daily) plus enzalutamide or placebo plus enzalutamide.[17]

The rationale for this combination is based on preclinical evidence of synergy. Androgen receptor signaling can regulate DNA repair pathways, and its inhibition with drugs like enzalutamide may induce a state of "BRCAness," impairing HRR function and thereby sensitizing tumor cells to PARP inhibition.

4.3.2. Efficacy Outcomes: rPFS and OS in All-Comers and HRR-Mutated Subgroups

The TALAPRO-2 trial met its primary and key secondary endpoints, demonstrating significant benefits for the combination therapy. The FDA's initial approval was based on the rPFS results in the HRR-mutated population, while subsequent final OS data have supported its broader clinical utility. A summary of the key efficacy outcomes is presented in Table 4.

Table 4: Summary of Efficacy Results from the TALAPRO-2 Trial

Efficacy Endpoint	Population	Talazoparib + Enzalutamide	Placebo + Enzalutamide	Hazard Ratio (HR) (95% CI)	p-Value	Source(s)
Median rPFS (Primary)	HRR-Mutated	Not Reached	13.8 months	HR: 0.45 (0.33, 0.61)	<0.0001	17
Median rPFS (Final)	All-Comers	33.1 months	19.5 months	HR: 0.667 (0.551, 0.807)	<0.0001	42
Median OS (Final)	HRR-Deficient	45.1 months	31.1 months	HR: 0.622 (0.475, 0.814)	0.0005	39
Median OS (Final)	All-Comers	45.8 months	37.0 months	HR: 0.796 (0.661, 0.958)	0.0155	42

The primary endpoint of radiographic progression-free survival (rPFS) was met with high statistical significance. In the HRR-mutated population, the combination of Talazoparib and enzalutamide resulted in a 55% reduction in the risk of radiographic progression or death compared to enzalutamide alone (HR 0.45; p<0.0001).[17] This profound benefit in the biomarker-selected group was the basis for the FDA's approval.[20] A significant rPFS benefit was also observed in the all-comer population (HR 0.63).[40]

Most importantly, the final analysis of overall survival demonstrated a statistically significant and clinically meaningful benefit. In the all-comer population, the combination therapy extended median OS by 8.8 months (45.8 months vs. 37.0 months; HR 0.796; p=0.0155).[39] As expected, the benefit was even greater in the HRR-deficient subgroup, where the combination extended median OS by approximately 14 months and reduced the risk of death by 38% (HR ~0.62).[39]

4.3.3. Subgroup Analyses and Clinical Implications

Subgroup analyses confirmed that the greatest magnitude of benefit was observed in patients with BRCA mutations (rPFS HR 0.20).[17] However, the demonstration of a significant OS benefit in the unselected "all-comer" population is a critical finding with broad clinical implications. It suggests that the synergistic mechanism between Talazoparib and enzalutamide may extend beyond the classic model of synthetic lethality in tumors with pre-existing HRR defects. The data suggest that ARPI therapy may induce a vulnerable state in a wider range of prostate cancers, sensitizing them to PARP inhibition. While the FDA approval was appropriately restricted to the HRR-mutated population where the benefit-risk ratio is most favorable [20], the final OS data provide a strong rationale for considering this combination as a new standard-of-care option for a much broader population of men with first-line mCRPC.[42]

V. Safety and Tolerability Profile

The safety profile of Talazoparib is well-characterized and is dominated by on-target hematological toxicities. Management of these adverse events is a central aspect of its clinical use.

5.1. Warnings and Precautions

The prescribing information for Talazoparib carries several important warnings and precautions that require diligent clinical monitoring.

5.1.1. Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML)

A rare but very serious risk associated with PARP inhibitors, including Talazoparib, is the development of therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). These conditions are often fatal. In clinical studies, MDS/AML was reported in approximately 0.4% of solid tumor patients treated with Talazoparib.[45] Many of these patients had confounding factors, such as prior exposure to platinum-based chemotherapy or other DNA-damaging agents.[47] Clinicians must monitor complete blood counts monthly. If a patient develops prolonged hematological toxicity (lasting more than 4 weeks), Talazoparib should be interrupted, and the patient should be referred to a hematologist for further investigation, including bone marrow analysis and cytogenetics. If MDS/AML is confirmed, Talazoparib must be permanently discontinued.[45]

5.1.2. Myelosuppression

Myelosuppression is the most common and clinically significant toxicity of Talazoparib.[32] It manifests as anemia (low red blood cells), neutropenia (low neutrophils), and/or thrombocytopenia (low platelets). Grade 3 or higher events are common and require active management.

• In the EMBRACA trial (breast cancer monotherapy): The incidence of Grade ≥3 adverse reactions was 39% for anemia, 21% for neutropenia, and 15% for thrombocytopenia.[1]
• In the TALAPRO-2 trial (prostate cancer combination therapy): The incidence of Grade ≥3 adverse reactions was 45% for anemia, 18% for neutropenia, and 8% for thrombocytopenia.[17] In this trial, 39% of patients receiving the combination required at least one red blood cell transfusion.[17]

Baseline and monthly monitoring of complete blood counts is mandatory throughout treatment. Treatment should not be initiated until patients have recovered from hematological toxicity caused by prior therapies.[13]

5.1.3. Embryo-Fetal Toxicity

Based on its mechanism of action (interfering with DNA repair) and findings in animal reproduction studies, Talazoparib can cause harm to a developing fetus and may lead to miscarriage.[13] Therefore, its use is contraindicated during pregnancy.

• Contraception: Females of reproductive potential must use effective contraception during treatment and for at least 7 months after the final dose. Male patients with female partners who are or could become pregnant must use effective contraception during treatment and for at least 4 months after the final dose.[45]
• Lactation: It is not known if Talazoparib passes into breast milk. Due to the potential for serious adverse reactions in a nursing infant, breastfeeding is not recommended during treatment and for at least 1 month after the final dose.[46]

5.2. Common Adverse Reactions

Beyond the major warnings, a range of other adverse reactions are commonly associated with Talazoparib. The most frequent events are hematologic and gastrointestinal in nature. Table 5 provides a summary of the most common adverse reactions observed in the pivotal EMBRACA trial.

Table 5: Incidence of Common (≥20%) and Grade ≥3 Adverse Reactions with Talazoparib (EMBRACA Trial)

Adverse Reaction	Talazoparib (Any Grade)	Chemotherapy (Any Grade)	Talazoparib (Grade ≥3)	Chemotherapy (Grade ≥3)	Source(s)
Hematologic
Anemia	53%	18%	39%	5%	1
Neutropenia	35%	43%	21%	35%	1
Thrombocytopenia	27%	7%	15%	2%	1
Non-Hematologic
Fatigue	62%	50%	-	-	32
Nausea	49%	47%	-	-	32
Headache	33%	22%	-	-	32
Vomiting	25%	23%	-	-	32
Alopecia (Hair Loss)	25%	28%	-	-	32
Diarrhea	22%	26%	-	-	32
Decreased Appetite	≥20%	-	-	-	32

The most common laboratory abnormalities (≥25%) reflect the myelosuppressive effects, with high rates of decreases in hemoglobin, leukocytes, lymphocytes, and platelets.[46]

5.3. Management of Adverse Reactions

The cornerstone of managing Talazoparib-related toxicity is dose modification, which may involve treatment interruption, dose reduction, or, in severe cases, permanent discontinuation.[9] The availability of multiple capsule strengths facilitates this management strategy. Specific, protocol-defined thresholds are used to guide these decisions, particularly for hematological toxicities. Table 6 outlines the recommended dose reduction schedules and the criteria for managing myelosuppression.

Table 6: Recommended Dose Modifications for Adverse Reactions

Parameter	Action	Source(s)
Dose Reduction Levels (Breast Cancer)
Starting Dose	1 mg once daily	10
First Reduction	0.75 mg once daily	10
Second Reduction	0.5 mg once daily	10
Third Reduction	0.25 mg once daily	10
Dose Reduction Levels (Prostate Cancer)
Starting Dose	0.5 mg once daily	10
First Reduction	0.35 mg once daily	10
Second Reduction	0.25 mg once daily	10
Third Reduction	0.1 mg once daily	10
Management of Hematologic Toxicity
Hemoglobin <8 g/dL	Withhold TALZENNA. Resume at a reduced dose when level resolves to ≥9 g/dL.	10
Platelet count <50,000/μL	Withhold TALZENNA. Resume at a reduced dose when count resolves to ≥75,000/μL.	10
Neutrophil count <1,000/μL	Withhold TALZENNA. Resume at a reduced dose when count resolves to ≥1500/μL.	10
Management of Non-Hematologic Toxicity
Grade 3 or 4	Withhold TALZENNA. Consider resuming at a reduced dose or discontinuing when toxicity resolves to ≤Grade 1.	10

Treatment with Talazoparib should be permanently discontinued if a patient requires more than three dose reductions.[9]

VI. Guidelines for Clinical Use

6.1. Approved Indications and Patient Selection

The use of Talazoparib is approved for specific, biomarker-defined patient populations, requiring genetic testing for patient selection.

• Breast Cancer: Talazoparib is indicated as a single agent for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative locally advanced or metastatic breast cancer.[5]
• Prostate Cancer: Talazoparib is indicated in combination with enzalutamide for the treatment of adult patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).[5]

For both indications, patient eligibility must be confirmed by an FDA-approved companion diagnostic test to detect the presence of the qualifying genetic mutations.[18]

6.2. Dosing and Administration

The recommended dosing for Talazoparib differs by indication.

• For Breast Cancer (monotherapy): The recommended starting dose is 1 mg taken orally once daily.[10]
• For Prostate Cancer (combination therapy): The recommended starting dose is 0.5 mg taken orally once daily. It is administered concurrently with enzalutamide (160 mg daily). Patients in this setting must also receive a gonadotropin-releasing hormone (GnRH) analog or have undergone a bilateral orchiectomy to maintain castrate levels of testosterone.[10]

For both indications, treatment should continue until disease progression or the development of unacceptable toxicity. The capsules can be taken with or without food and must be swallowed whole. If a patient vomits or misses a dose, they should not take an additional dose but should resume with the next scheduled dose at the usual time.[9]

6.3. Dose Modifications for Special Populations and Drug Interactions

Specific dose adjustments are required for patients with renal impairment and for those taking certain interacting medications. These adjustments are critical for maintaining a safe exposure level. Table 7 summarizes these required modifications.

Table 7: Recommended Dosing Adjustments for Renal Impairment and Drug Interactions

Condition	Indication	Recommended TALZENNA Dose	Source(s)
Moderate Renal Impairment (CLcr​ 30-59 mL/min)	Breast Cancer	0.75 mg once daily	9
	Prostate Cancer	0.35 mg once daily	10
Severe Renal Impairment (CLcr​ 15-29 mL/min)	Breast Cancer	0.5 mg once daily	9
	Prostate Cancer	0.25 mg once daily	10
Coadministration with Strong P-gp Inhibitors*	Breast Cancer	0.75 mg once daily	9

*Strong P-gp inhibitors include amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil. For other P-gp or BCRP inhibitors, dose reduction is not mandated, but increased monitoring for adverse reactions is recommended.[27]

Talazoparib is a substrate of the P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) efflux transporters.[26] Coadministration with drugs that inhibit these transporters can increase plasma concentrations of Talazoparib, thereby increasing the risk of toxicity.[15] If concurrent use with a potent P-gp inhibitor cannot be avoided, the dose of Talazoparib must be reduced as specified. When the inhibitor is discontinued, the Talazoparib dose should be increased back to the original dose after 3-5 half-lives of the interacting drug have passed.[9]

VII. Regulatory and Market History

The development and commercialization of Talazoparib involved several pharmaceutical companies. It was initially developed by BioMarin Pharmaceutical Inc. In August 2015, Medivation Inc. acquired the worldwide rights to the compound. Subsequently, in 2016, Pfizer acquired Medivation and now holds the global marketing rights for Talazoparib under the brand name Talzenna®.[1]

Talazoparib has received approvals from major regulatory agencies based on the strength of its pivotal clinical trial data.

• U.S. Food and Drug Administration (FDA):
• Breast Cancer: Approved on October 16, 2018, for the treatment of gBRCAm, HER2-negative advanced breast cancer. The application was granted Priority Review status.[1]
• Prostate Cancer: Approved on June 20, 2023, for use in combination with enzalutamide for HRR gene-mutated mCRPC. This application was also granted Priority Review.[17]
• European Medicines Agency (EMA):
• Breast Cancer: The European Commission granted marketing authorization in June 2019.[1]
• Prostate Cancer: The combination with enzalutamide was approved in January 2024.[1]

Across all major global markets, including the United States, European Union, Canada, United Kingdom, and Australia, Talazoparib is classified as a prescription-only medicine (℞-only).[1]

VIII. Conclusion

Talazoparib (Talzenna®) represents a significant advancement in the field of precision oncology, solidifying the role of PARP inhibitors as a cornerstone of therapy for cancers with underlying DNA damage repair deficiencies. Its defining feature is an exceptionally potent dual mechanism of action, combining catalytic inhibition with profound PARP trapping, which drives its robust clinical efficacy. This potency, however, is directly linked to its primary and dose-limiting toxicity of myelosuppression, creating a clear and predictable relationship between its on-target mechanism, therapeutic benefit, and safety profile.

The clinical development program, highlighted by the pivotal EMBRACA and TALAPRO-2 trials, has unequivocally established its value. In gBRCA-mutated advanced breast cancer, it offers a significant progression-free survival and quality-of-life advantage over standard chemotherapy. In metastatic castration-resistant prostate cancer, its combination with enzalutamide has set a new standard of care for HRR-mutated disease by delivering a clinically meaningful overall survival benefit.

The successful clinical application of Talazoparib hinges on a comprehensive understanding of its properties. This includes mandatory biomarker testing for patient selection, diligent monitoring for hematological toxicities, and adherence to established guidelines for dose modification in response to adverse events or in specific populations, such as those with renal impairment. As research continues, the full potential of Talazoparib, both as a monotherapy and in novel combinations, will likely expand, further refining its role in the treatment of cancers vulnerable to the principle of synthetic lethality.

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