Underutilization of PARP Inhibitors in Metastatic Prostate Cancer With BRCA1/2 Alterations: Insights from a US Real-World Cohort

Highlight

– Approximately 51% of patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 alterations received PARP inhibitors in a large US retrospective cohort.
– Medicare insurance was associated with higher likelihood of PARP inhibitor receipt compared to commercial insurance.
– No statistically significant difference in PARP inhibitor use was observed between community and academic oncology practices.
– Nearly half of eligible patients did not receive PARP inhibitors, underscoring the need to improve awareness and access to targeted therapies in this population.

Study Background and Disease Burden

Prostate cancer remains a leading cause of cancer-related morbidity and mortality among men worldwide. Metastatic castration-resistant prostate cancer (mCRPC), the advanced stage refractory to androgen deprivation therapy, presents significant therapeutic challenges. A subset of mCRPC patients harbor germline or somatic alterations in the DNA repair genes BRCA1 and BRCA2, which are associated with aggressive disease course but also render tumors susceptible to targeted therapies.

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors, such as olaparib and rucaparib, have demonstrated improved progression-free and overall survival as monotherapy or combined with androgen receptor pathway inhibitors in landmark phase III clinical trials involving patients with mCRPC and deleterious BRCA1/2 mutations. These approvals, beginning with rucaparib in 2020, represent a paradigm shift by introducing precision medicine in prostate cancer management. However, real-world data on the adoption of PARP inhibitors among eligible patients remain sparse.

Understanding treatment patterns is critical for identifying barriers and disparities in access to these life-prolonging agents to optimize outcomes for patients with BRCA-mutated mCRPC.

Study Design

This retrospective cohort study utilized the deidentified Flatiron Health electronic health record-derived database, encompassing clinical data from US academic and community oncology practices. The cohort included adult male patients diagnosed with mCRPC harboring evidence of BRCA1 or BRCA2 alterations. Inclusion required survival beyond August 15, 2020, which is three months after the US Food and Drug Administration (FDA) approval of rucaparib for this indication.

The data cutoff was May 31, 2024. Patient-level variables captured at mCRPC diagnosis included age, race and ethnicity, insurance status (commercial vs Medicare), and type of practice setting (community vs academic). The primary outcome was receipt of any PARP inhibitor (olaparib, rucaparib, or others) during the study period.

Multivariable logistic regression models assessed associations between patient and clinical factors with PARP inhibitor receipt, controlling for potential confounders. Statistical analyses were conducted from September 2024 to May 2025.

Key Findings

Among 24,105 patients with metastatic prostate cancer in the dataset, 443 men (median age 72 years, interquartile range 65–79 years) met inclusion criteria with documented BRCA1/2 alterations. Of these, 227 (51.2%) received PARP inhibitors, while 216 (48.8%) did not receive PARP-targeted therapy.

Insurance Status:
The analysis revealed a significant disparity related to insurance coverage. Patients insured through Medicare were nearly twice as likely to receive PARP inhibitors compared to those with commercial insurance (odds ratio [OR]: 1.91; 95% confidence interval [CI]: 1.02–3.66; P = 0.047). This finding suggests variations in formulary coverage, reimbursement policies, or prescribing patterns influenced by payer type.

Practice Setting:
There was a trend towards higher PARP inhibitor use among patients treated in community oncology practices compared with academic centers (OR: 1.64; 95% CI: 1.00–2.70; P = 0.05). Although this result approached but did not reach statistical significance, it indicates comparable accessibility across diverse clinical environments.

Age, race, and ethnicity did not show significant associations with receipt of PARP inhibitors after adjustment for other variables, suggesting equitable treatment across demographic groups within this cohort.

The substantial proportion (~49%) of patients with documented BRCA alterations who did not receive PARP inhibitors despite evidence supporting efficacy raises concerns. Potential contributing factors include lack of provider awareness of genetic testing or PARP inhibitor indications, patient comorbidities, financial toxicity, or logistical challenges in accessing molecular diagnostics and targeted therapy.

Expert Commentary

These findings represent one of the first large-scale real-world examinations of PARP inhibitor uptake in BRCA-mutated mCRPC, highlighting important gaps between clinical trial evidence and routine practice. The observed underutilization underscores the need to enhance guideline dissemination, molecular diagnostic infrastructure, and payer alignment to broaden access.

As the therapeutic landscape evolves with ongoing trials combining PARP inhibitors with immunotherapy or novel androgen pathway inhibitors, timely identification of eligible patients is paramount. Clinicians should prioritize comprehensive genomic profiling early in disease to guide personalized therapy decisions.

Limitations of this retrospective study include reliance on electronic health record data, which may incompletely capture mutation status or treatment administration. Additionally, reasons for non-treatment with PARP inhibitors were not explored and warrant further qualitative investigation.

Conclusion

In summary, this retrospective cohort study reveals that only about half of patients with mCRPC harboring BRCA1/2 alterations received PARP inhibitor therapy despite compelling trial evidence demonstrating survival benefits. Insurance type influenced treatment receipt, whereas practice setting did not significantly affect access. These data emphasize critical gaps in the implementation of precision oncology for advanced prostate cancer and call for coordinated efforts to increase awareness, streamline genetic testing, and ensure equitable access to targeted therapies that improve patient outcomes.

References

Ostrowski M, Jo Y, Hage Chehade C, et al. Receipt of PARP Inhibitors in Patients With Metastatic Prostate Cancer Harboring BRCA1/2 Alterations. JAMA Netw Open. 2025;8(10):e2534968. doi:10.1001/jamanetworkopen.2025.34968

Antonarakis ES, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020;382(22):2091-2102.

Khalaf DJ, et al. Molecular Profiling of Advanced Prostate Cancer and Targeted Therapeutic Options. Nat Rev Clin Oncol. 2023;20(3):155-170.

FDA. Rucaparib approval for mCRPC. 2020. Available at https://www.fda.gov

AI-friendly Visual Prompt:
“An oncologist consulting a middle-aged male patient with metastatic prostate cancer, reviewing genomic test results and treatment options on a digital tablet, with a hospital and DNA helix graphic in the background.”