What is the role of Talazoparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) in the treatment of metastatic castration-resistant prostate cancer (mCRPC)?

Talazoparib for Metastatic Castration-Resistant Prostate Cancer

Talazoparib plus enzalutamide is FDA-approved and strongly recommended (NCCN Category 1) for first-line treatment of mCRPC in patients with HRR gene mutations (BRCA1, BRCA2, ATM, ATR, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) who have not received prior novel hormone therapy or docetaxel in the CRPC setting. 1, 2

Patient Selection Algorithm

Strongest Indication (Category 1):

• Treatment-naïve mCRPC patients with documented HRR gene mutations (germline and/or somatic) who have NOT received:
  • Prior novel hormone therapy in the CRPC setting
  • Prior docetaxel in the CRPC setting 1

Acceptable Indication (Category 2A):

• Patients with HRR gene mutations who received prior docetaxel in the castration-sensitive setting but no prior novel hormone therapy in CRPC 1

Controversial/Weak Indication (Category 2B):

• Patients who received prior novel hormone therapy without prior docetaxel—benefit over PARP inhibitor monotherapy is unproven in this setting 1

Efficacy by Mutation Type

The benefit of talazoparib varies dramatically based on the specific HRR mutation:

BRCA1/2 Mutations (Strongest Benefit):

• 77% reduction in radiographic progression or death (HR 0.23; 95% CI 0.10-0.53) 1
• Median radiographic PFS not reached vs 21.9 months with enzalutamide alone 1, 3

Non-BRCA HRR Mutations (Modest Benefit):

• 34% reduction in progression risk (HR 0.66; 95% CI 0.39-1.12; not statistically significant) 1
• The benefit is less compelling than with BRCA mutations 1

HRR-Proficient/Unknown Status:

• 30% reduction in progression risk (HR 0.70; 95% CI 0.54-0.89) 1
• This reflects synthetic lethality from androgen receptor inhibition downregulating DNA repair genes 4

Critical Toxicity Considerations

The combination carries significant hematologic toxicity requiring proactive management:

Expected Adverse Events:

• Grade ≥3 anemia in 46% of patients—the most common serious toxicity 1, 3
• Grade ≥3 neutropenia and thrombocytopenia occur but are less frequent 1, 5
• Fatigue is common but rarely severe 1, 3

Treatment Modifications Required:

• Dose interruptions in 75% of patients (vs 23% with enzalutamide alone) 1
• Dose reductions in 56% of patients (vs 7% with enzalutamide alone) 1
• Only 8% discontinued due to anemia, as most cases improved with dose reduction 3

Monitoring Requirements:

• Complete blood count monitoring is mandatory throughout treatment 4, 6
• Type and screen availability with transfusion support readiness is required 6

Genomic Testing Requirements

All patients with mCRPC being considered for talazoparib must undergo both germline and somatic genomic testing with next-generation sequencing technologies before treatment initiation. 1

• Testing should identify pathogenic mutations in the 12 specified HRR genes 1
• Somatic testing is particularly important as tumor mutations may differ from germline 1
• Expertise in interpretation must be readily available 1

Common Pitfalls to Avoid

1. Do not use talazoparib monotherapy in first-line mCRPC—the FDA approval and NCCN recommendation are specifically for the combination with enzalutamide 1, 2

2. Do not assume all HRR mutations respond equally—BRCA1/2 mutations show dramatically superior benefit compared to non-BRCA HRR alterations 1

3. Do not underestimate hematologic toxicity—three-quarters of patients will require dose interruptions, so establish monitoring protocols and transfusion access before starting therapy 1, 4

4. Do not use in patients with prior novel hormone therapy without careful consideration—the benefit in this population is controversial (Category 2B) as the HR was nonsignificant (0.57; 95% CI 0.28-1.16) 1

Quality of Life Data

Despite significant toxicity, talazoparib does not negatively impact health-related quality of life:

• EQ-5D-5L Index improved by 0.05 in all patients and 0.07 in BRCA1/2 subset 7
• Worst pain improved from baseline (mean change -1.08 overall, -1.15 in BRCA1/2 subset) 7
• 84% probability of no pain deterioration by month 12 7

Comparison with Other PARP Inhibitor Combinations

The NCCN also recommends:

• Olaparib plus abiraterone for BRCA1/2 mutations (Category 1) 1, 4
• Niraparib plus abiraterone for BRCA1/2 mutations (Category 1) 1, 4

The choice between these combinations should consider:

• Specific androgen receptor inhibitor preference (enzalutamide vs abiraterone)
• Toxicity profiles—talazoparib has higher rates of dose modifications than olaparib 1, 6
• Mutation type—all show strongest benefit in BRCA1/2 mutations 1, 4