PARP inhibitors in prostate cancer: time to narrow patient selection?

Markowski, Mark C.; Antonarakis, Emmanuel S.

doi:10.1080/14737140.2020.1781622

Cited by 4 publications

(2 citation statements)

References 23 publications

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“…In conclusion, optimal treatment selection towards or against PARP inhibitor use (and potentially also platinum-based chemotherapies) in prostate cancer requires further refinement ( 47 ). While the selection of patients based on the presence or absence of a particular HR gene mutation (e.g.…”

Section: Discussionmentioning

confidence: 99%

Homologous recombination deficiency (HRD) score in germline BRCA2- versus ATM-altered prostate cancer

et al. 2021

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The homologous recombination deficiency (HRD) score integrates three DNA-based measures of genomic instability, and has been understudied in prostate cancer. Given the recent FDA-approval of two PARP inhibitors for prostate cancer, HRD score analysis could help to refine treatment selection. We assessed HRD score (defined as the sum of loss-of-heterozygosity, telomeric allelic imbalance, and large-scale state transitions) in three cohorts of primary prostate cancer, including a Johns Hopkins University (JHU) cohort with germline mutations in BRCA2 , ATM or CHEK2 (n=64), the TCGA cohort (n=391), and the PROGENE cohort (n=102). In the JHU cohort, tumors with germline BRCA2 mutations had higher HRD scores (median=27) than those with germline ATM or CHEK2 mutations (median=16.5 [p=0.029] and 9 [p<0.001], respectively). For TCGA tumors without underlying HR pathway mutations, the median HRD score was 11, significantly lower than ovarian carcinoma lacking BRCA1/2 mutations (median=28). In the absence of HR gene mutations, the median HRD score was unexpectedly higher among prostate cancers with TP53 mutations versus those without (17 vs 11; p=0.015); this finding was confirmed in the PROGENE cohort (24 vs 16; p=0.001). Finally, among eight BRCA2 -altered patients who received olaparib, progression-free survival trended longer in those with HRD scores above versus below the median (14.9 vs 9.9 months). We conclude that HRD scores are low in primary prostate cancer and higher in cases with germline BRCA2 or somatic TP53 mutations. Germline BRCA2 -altered cases have significantly higher HRD scores than germline ATM -altered or CHEK2 -altered cases, consistent with the lower efficacy of PARP inhibitors among the latter.

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Section: Discussionmentioning

confidence: 99%

Homologous recombination deficiency (HRD) score in germline BRCA2- versus ATM-altered prostate cancer

et al. 2021

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“…The median duration of response was not reached at the time of analysis (between 1.7 to 24 months) [ 46 ]. In the patients without BRCA mutations, the RR was clearly lower [ 47 , 48 ]. This study led to FDA approval of rucaparib in 2020, conditional on the results of the phase III trial TRITON3.…”

Section: Clinical Development Of Parp Inhibitors In Prostate Cancermentioning

confidence: 99%

PARP Inhibitors: A New Horizon for Patients with Prostate Cancer

et al. 2022

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The introduction of PARP inhibitors (PARPi) in prostate cancer is a milestone and provides a pathway to hope in fighting this disease. It is the first time that drugs, based on the concept of synthetic lethality, have been approved for prostate cancer. In addition, it is also the first time that genetic mutation tests have been included in the therapeutic algorithm of this disease, representing a significant step forward for precision and personalized treatment of prostate cancer. The objectives of this review are: (1) understanding the mechanism of action of PARPi in monotherapy and combinations; (2) gaining insights on patient selection for PARPi; (3) exposing the pivotal studies that have allowed its approval, and; (4) offering an overview of the ongoing trials. Nevertheless, many unsolved questions remain, such as the number of patients who could potentially benefit from PARPi, whether to use PARPi in monotherapy or in combination, and when is the best time to use them in advanced or localized disease. To answer these and other questions, many clinical trials are underway. Some of them have recently demonstrated promising results that may favor the introduction of new combinations in metastatic castration-resistant prostate cancer.

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