Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and <i>BRCA1, BRCA2</i>, or <i>ATM</i> Alterations Identified by Testing Circulating Tumor DNA

Matsubara, Nobuaki; Bono, Johann S. de; Olmos, David; Procopio, Giuseppe; Kawakami, Satoru; Ürün, Yüksel; Alphen, Robbert van; Fléchon, Aude; Carducci, Michael A.; Choi, Young Deuk; Hotte, Sébastien J.; Korbenfeld, Ernesto; Kramer, Gero; Agarwal, Neeraj; N., Kim; Dearden, Simon; Gresty, Christopher; Kang, Jinyu; Poehlein, Christian; Hussain, Maha

doi:10.1158/1078-0432.ccr-21-3577

Cited by 22 publications

(9 citation statements)

References 44 publications

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“…Second, a recent exploratory analysis of the PROfound study evaluated the efficacy of olaparib in patients with BRCA/ATM mutations investigated by liquid biopsy, showing that the clinical outcome endpoints were similar to those reached in the cohort in which mutations had been studied with somatic testing [3,56]. Therefore, this study highlights that the liquid biopsy technique could be a test with the same prognostic and predictive value as somatic testing.…”

Section: Discussionmentioning

confidence: 60%

Frequency of Germline and Somatic BRCA1 and BRCA2 Mutations in Prostate Cancer: An Updated Systematic Review and Meta-Analysis

Valsecchi

Dionisio

Panepinto

et al. 2023

Cancers

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In prostate cancer (PC), the presence of BRCA somatic and/or germline mutation provides prognostic and predictive information. Meta-analysis aims to estimate the frequency of BRCA mutations in patients with PC (PCp). In November 2022, we reviewed literature searching for all articles testing the proportion of BRCA mutations in PCp, without explicit enrichment for familiar risk. The frequency of germline and somatic BRCA1 and/or BRCA2 mutations was described in three stage disease populations (any/metastatic/metastatic castration-resistant PC, mCRPC). Out of 2253 identified articles, 40 were eligible. Here, 0.73% and 1.20% of any stage PCp, 0.94% and 1.10% of metastatic PCp, and 1.21% and 1.10% of mCRPC patients carried germline and somatic BRCA1 mutation, respectively; 3.25% and 6.29% of any stage PCp, 4.51% and 10.26% of metastatic PCp, and 3.90% and 10.52% of mCRPC patients carried germline and somatic BRCA2 mutation, respectively; and 4.47% and 7.18% of any stage PCp, 5.84% and 10.94% of metastatic PCp, and 5.26% and 11.26% of mCRPC patients carried germline and somatic BRCA1/2 mutation, respectively. Somatic mutations are more common than germline and BRCA2 are more common than BRCA1 mutations; the frequency of mutations is higher in the metastatic setting. Despite that BRCA testing in PC is now standard in clinical practice, several open questions remain.

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Section: Discussionmentioning

confidence: 60%

Frequency of Germline and Somatic BRCA1 and BRCA2 Mutations in Prostate Cancer: An Updated Systematic Review and Meta-Analysis

Valsecchi

Dionisio

Panepinto

et al. 2023

Cancers

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“…Previous studies have validated the feasibility of ctDNA in detecting mutations of HRR genes in breast and prostate cancers [33][34][35], but relevant studies are scarce in ovarian cancer. Our study obtained high concordance between ctDNA and tumour samples to detect BRCA /HRR mutations.…”

Section: Discussionmentioning

confidence: 99%

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer

Li,

Peng,

Zhu

et al. 2024

BMC Med

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Background The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. Methods HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan–Meier method was utilised to analyse progression-free survival (PFS). Results This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5–22.1) versus 9.2 months (95% CI: 7.5–13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4–18.2) versus 22.2 months (95% CI: 18.3–NA)]. Conversely, positive PD-L1 expression on immune cells was associated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9–NA) versus 8.3 months (95% CI: 6.7–13.8)]. Conclusions HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. Trial registration NCT03534453. Registered at May 23, 2018.

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“…ATM is crucial for DNA repair and cell cycle control, and mutations can lead to increased cancer risk. The PROfound study showed improved OS with Olaparib for mCRPC patients with BRCA1/2 or ATM mutations, leading to FDA approval for Olaparib in these cases in May 2020 ( 30 ). ATM status is also key in deciding on platinum-based chemotherapy or immunotherapy, as they depend on the cell’s ability to repair DNA.…”

Section: Discussionmentioning

confidence: 99%

Case report and literature review of rezvilutamide in the treatment of hormone-sensitive prostate cancer

Zhang,

Ren,

Kang

et al. 2024

Front. Oncol.

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BackgroundProstate cancer represents a major health concern worldwide, with the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) and locally advanced prostate cancer posing a particular challenge. Rezvilutamide, a new androgen receptor antagonist from China, has shown early promise; however, its real-world effectiveness and safety profile require further evidence. This case series evaluates the preliminary clinical outcomes of rezvilutamide in combination with androgen deprivation therapy (ADT), focusing on PSA response and radiological findings across various stages of prostate cancer in four patients.Case descriptionCase 1 details a 68-year-old male with low-volume mHSPC who exhibited a positive therapeutic response, demonstrated by decreasing PSA levels and improved radiographic results, despite experiencing mild side effects related to the drug. Case 2 describes a 71-year-old male with high-volume mHSPC who had a favorable outcome, with no significant changes in tumor size or metastatic spread and no negative reactions to the drug. Case 3 involves a 55-year-old male with locally advanced prostate cancer, who saw a reduction in PSA levels and a small decrease in tumor volume, yet with ongoing bladder involvement. Genetic testing showed no significant mutations. Case 4 presents a 74-year-old male with extensive metastatic disease who initially responded to the treatment but later exhibited disease advancement and an ATM gene mutation, signaling a shift to metastatic castration-resistant prostate cancer (mCRPC). This finding underscores the crucial role of genetic testing in directing future treatment, with therapies such as olaparib or chemotherapy being advised.ConclusionsRezvilutamide has shown a potential benefit in the management of mHSPC and locally advanced prostate cancer, generally with a mild safety profile. Initial positive responses, particularly in PSA decline and radiographic progression, are promising. Nevertheless, the varying responses, notably concerning genetic mutations, highlight the necessity for tailored treatment approaches. Due to the small cohort and brief follow-up period, more extensive research with larger populations and prolonged monitoring is essential to conclusively determine the benefits and safety of rezvilutamide. The utilization of genetic insights is key to refining treatment decisions and enhancing outcomes for patients with advanced prostate cancer.

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Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and BRCA1, BRCA2, or ATM Alterations Identified by Testing Circulating Tumor DNA

Cited by 22 publications

References 44 publications

Frequency of Germline and Somatic BRCA1 and BRCA2 Mutations in Prostate Cancer: An Updated Systematic Review and Meta-Analysis

Frequency of Germline and Somatic BRCA1 and BRCA2 Mutations in Prostate Cancer: An Updated Systematic Review and Meta-Analysis

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer

Case report and literature review of rezvilutamide in the treatment of hormone-sensitive prostate cancer

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