RESUMEN
After recent approvals, poly-adenosine diphosphate [ADP]-ribose polymerase inhibitors (PARPis) have emerged as a frontline treatment for metastatic castration-resistant prostate cancer (mCRPC). Unlike their restricted use in breast or ovarian cancers, where approval is limited to those with BRCA1/2 alterations, PARPis in mCRPC are applied across a broader spectrum of genetic aberrations. Key findings from the phase III PROPEL trial suggest that PARPis' accessibility may broaden, even without mandatory testing. An increasing body of evidence underscores the importance of distinct alterations in homologous recombination repair (HRR) genes, revealing unique sensitivities to PARPis. Nonetheless, despite the initial effectiveness of PARPis in treating BRCA-mutated tumors, resistance to therapy is frequently encountered. This review aims to discuss patient stratification based on biomarkers and genetic signatures, offering insights into the nuances of first-line PARPis' efficacy in the intricate landscape of mCRPC.
Asunto(s)
Proteína BRCA1 , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Femenino , Humanos , Proteína BRCA1/genética , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Medicina de Precisión , Proteína BRCA2/genética , Poli(ADP-Ribosa) PolimerasasRESUMEN
Prostate cancer (PCa) is the most common cancer in men worldwide. Despite better and more intensive treatment options in earlier disease stages, a large subset of patients still progress to metastatic castration-resistant PCa (mCRPC). Recently, poly-(ADP-ribose)-polymerase (PARP)-inhibitors have been introduced in this setting. The TALAPRO-2 and PROpel trials both showed a marked benefit of PARPi in combination with an androgen receptor signaling inhibitor (ARSI), compared with an ARSI alone in both the homologous recombination repair (HRR)-mutated, as well as in the HRR-non-mutated subgroup. In this review, we present a comprehensive overview of how maximal AR-blockade via an ARSI in combination with a PARPi has a synergistic effect at the molecular level, leading to synthetic lethality in both HRR-mutated and HRR-non-mutated PCa patients. PARP2 is known to be a cofactor of the AR complex, needed for decompacting the chromatin and start of transcription of AR target genes (including HRR genes). The inhibition of PARP thus reinforces the effect of an ARSI. The deep androgen deprivation caused by combining androgen deprivation therapy (ADT) with an ARSI, induces an HRR-like deficient state, often referred to as "BRCA-ness". Further, PARPi will prevent the repair of single-strand DNA breaks, leading to the accumulation of DNA double-strand breaks (DSBs). Due to the induced HRR-deficient state, DSBs cannot be repaired, leading to apoptosis.
RESUMEN
BACKGROUND: a specific subset of metastatic triple-negative breast cancers (mTNBC) is characterized by homologous recombination deficiency (HRD), leading to enhanced sensitivity to platinum-based chemotherapy. Apart from mutations in BRCA1/2 genes, the evaluation of other HRD-related alterations has been limited to date. As such, we analyzed data from mTNBC patients enrolled in the ProfiLER-01 study to determine the prevalence of alterations in homologous recombination-related (HRR) genes and their association with platinum sensitivity. METHODS: next-generation sequencing and promoter methylation of BRCA1 and RAD51C were performed on tumors from patients with mTNBC, using a panel of 19 HRR genes. Tumors were separated into three groups based on their molecular status: mutations in BRCA1/2, mutations in other HRR genes (BRCA1/2 excluded) or BRCA1/RAD51C promoter methylation and the absence of molecular alterations in HRR genes (groups A, B and C, respectively). Sensitivity to platinum-based chemotherapy was evaluated through the radiological response. RESULTS: mutations in BRCA1/2 were detected in seven (13.5%) patients, while alterations in other HRR genes or hypermethylation in BRCA1 or RAD51C were reported in 16 (30.7%) patients; furthermore, no alteration was found in the majority of patients (n = 29; 55.8%). Among 27 patients who received platinum-based chemotherapy, the disease control rate was 80%, 55% and 18% (groups A, B and C, respectively; p = 0.049). Regarding group B, patients with disease control exhibited mutations in FANCL, FANCA and the RAD51D genes or RAD51C methylation; Conclusion: mutations in HRR genes and epimutations in RAD51C were associated with disease control through platinum-based chemotherapy. As such, apart from well-characterized alterations in BRCA1/2, a more comprehensive evaluation of HRD should be considered in order to enlarge the selection of patients with mTNBC that could benefit from platinum-based chemotherapy.
RESUMEN
INTRODUCTION: In prostate cancer , there has recently been an emerging interest in mutations in genes belonging to the homologous recombination repair (HRR) pathway and in the inhibition of poly (ADP-ribose) polymerase (PARP) proteins. AREAS COVERED: Mutations in the HRR genes, including BRCA1, BRCA2, and Ataxia-Telangiesctasia mutated (ATM), have been reported in prostate cancer, with different incidence in the localized and advanced settings. The PARP enzyme complex is involved in repair of DNA damage and its inhibition causes the accumulation of DNA mutations in HRR deficient cells. Several PARP inhibitors (PARPi) are under development, such as olaparib, talazoparib, niraparib, rucaparib, and veliparib. In metastatic castration resistant prostate cancer (mCRPC), olaparib has been the most studied and its clinical efficacy has been validated in a phase III clinical trial. Rucaparib and niraparib have also shown promising results in the preliminary analyzes of two phase II trials, while talazoparib is currently under development. EXPERT OPINION: PARPi have become part of the treatment of mCRPC. Early results of combination therapy with PARPi and new hormonal therapy are promising and are supported by a strong biological rationale. Current results need to be validated in randomized phase III-controlled trials in order to translate the use of PARPi into real world practice.