Combination niraparib and abiraterone for HRR-altered metastatic castration-resistant prostate cancer
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Abstract:
Metastatic prostate cancer remains incurable. Though significant progress has been made in the field, the search for agents that improve outcomes for patients is ongoing. Several clinical trials have explored the benefit of combining PARP inhibitors (PARPi) with androgen receptor pathway inhibitors (ARPIs) for metastatic castrate resistant prostate cancer (mCRPC), especially those cancers with alterations in homologous recombination repair (HRR) genes. Niraparib, a highly selective inhibitor of PARP1 and PARP2, has been shown to confer a radiographic progression-free survival benefit in the treatment of mCRPC with HRR-associated gene alterations, particularly BRCA1 and BRCA2 (BRCA1/2), when combined with abiraterone acetate plus prednisolone (AAP). This combination has recently been approved in the USA, Canada and Europe for patients with mCRPC and a BRCA1/2 gene mutation. This review summarizes the evidence with regards to the pharmacologic activity and clinical efficacy of niraparib with a specific focus on its efficacy in combination with AAP in mCRPC patients with HRR alterations.Keywords:
Abiraterone acetate
PARP inhibitor
Enzalutamide
PARP1
Abiraterone
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Enzalutamide
Abiraterone acetate
Abiraterone
Cabazitaxel
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Enzalutamide
Abiraterone
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Enzalutamide
Abiraterone acetate
Abiraterone
Sequence (biology)
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Enzalutamide
Abiraterone
splice
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<div>Abstract<p>Purpose: We present long-term outcomes from two randomized studies (STAMP [with abiraterone, NCT01487863] and STRIDE [with enzalutamide, NCT01981122]) that were performed to study the impact of sequential or concurrent administration of ARTAs on sipuleucel-T immune response and overall survival (OS) in metastatic castration-resistant prostate cancer. Experimental design: Sipuleucel-T was administered per current prescribing information. Results from STRIDE are presented together with updated STAMP results. Survival status of patients was updated using demographic information to query the National Death Index (NDI). Kaplan–Meier methodology was used to analyze survival. Results: Updated data reduced patient censoring in each study compared with the original analyses; the 95% CIs for OS are now estimable. Updated median OS (95% CI) is 33.3 (24.1–40.7) months for STAMP and 32.5 (26.0–45.1) months for STRIDE. There was no notable impact on median OS (hazard ratio [HR], 0.727 [0.458–1.155]; P=0.177, reference = STRIDE). OS with sequential administration was similar to concurrent administration (NDI update: HR, 0.963 [0.639–1.453]; P=0.845, reference = concurrent arm). Sipuleucel-T potency, measured as antigen-presenting cell activation, was higher in subsequent infusions compared with the first infusion. Humoral responses (IgG + IgM antibody titers) to PA2024 and prostatic acid phosphatase were significantly elevated vs baseline. No new safety signals were observed. Conclusions: Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs.</p></div>
Enzalutamide
Abiraterone acetate
STRIDE
Abiraterone
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Enzalutamide
Abiraterone acetate
Abiraterone
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Enzalutamide
Abiraterone
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Background
The approval of new therapies for metastatic castration-resistant prostate cancer (mCRPC), including the oral agents abiraterone acetate and enzalutamide, has altered the standard of care for patients with mCRPC. Little information exists regarding the sequences in which new therapies for mCRPC with evidence of survival benefits are used.
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Abiraterone acetate
Abiraterone
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<p>Supplementary Data for Antonarakis et al</p>
Enzalutamide
Abiraterone acetate
Abiraterone
STRIDE
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Enzalutamide
Abiraterone
Abiraterone acetate
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