PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Unraveling the Therapeutic Landscape
The treatment landscape of metastatic prostate cancer (mPCa) is rapidly evolving with the recent approvals of poly-ADP ribose polymerase inhibitors (PARPis) as monotherapy or as part of combination therapy with androgen receptor pathway inhibitors in patients with metastatic castration-resistant pro...
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MDPI AG
2024-01-01
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| Online Access: | https://www.mdpi.com/2075-1729/14/2/198 |
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| author | Ashaar Al-Akhras Chadi Hage Chehade Arshit Narang Umang Swami |
| author_facet | Ashaar Al-Akhras Chadi Hage Chehade Arshit Narang Umang Swami |
| author_sort | Ashaar Al-Akhras |
| collection | DOAJ |
| description | The treatment landscape of metastatic prostate cancer (mPCa) is rapidly evolving with the recent approvals of poly-ADP ribose polymerase inhibitors (PARPis) as monotherapy or as part of combination therapy with androgen receptor pathway inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC). Already part of the therapeutic armamentarium in different types of advanced cancers, these molecules have shaped a new era in mPCa by targeting genomic pathways altered in these patients, leading to promising responses. These agents act by inhibiting poly-ADP ribose polymerase (PARP) enzymes involved in repairing single-strand breaks in the DNA. Based on the PROfound and TRITON3 trials, olaparib and rucaparib were respectively approved as monotherapy in pretreated patients with mCRPC and alterations in prespecified genes. The combinations of olaparib with abiraterone (PROpel) and niraparib with abiraterone (MAGNITUDE) were approved as first-line options in patients with mCRPC and alterations in <i>BRCA1/2</i>, whereas the combination of talazoparib with enzalutamide (TALAPRO-2) was approved in the same setting in patients with alterations in any of the HRR genes, which are found in around a quarter of patients with advanced prostate cancer. Additional trials are already underway to assess these agents in an earlier hormone-sensitive setting. Future directions will include refining the treatment sequencing in patients with mCRPC in the clinic while taking into account the financial toxicity as well as the potential side effects encountered with these therapies and elucidating their mechanism of action in patients with non-altered HRR genes. Herein, we review the biological rationale behind using PARPis in mCRPC and the key aforementioned clinical trials that paved the way for these approvals. |
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| last_indexed | 2024-03-07T22:24:27Z |
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| series | Life |
| spelling | doaj.art-2047f63304e4412889809a1f9f51b2902024-02-23T15:24:36ZengMDPI AGLife2075-17292024-01-0114219810.3390/life14020198PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Unraveling the Therapeutic LandscapeAshaar Al-Akhras0Chadi Hage Chehade1Arshit Narang2Umang Swami3Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, JordanDivision of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USADivision of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USADivision of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USAThe treatment landscape of metastatic prostate cancer (mPCa) is rapidly evolving with the recent approvals of poly-ADP ribose polymerase inhibitors (PARPis) as monotherapy or as part of combination therapy with androgen receptor pathway inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC). Already part of the therapeutic armamentarium in different types of advanced cancers, these molecules have shaped a new era in mPCa by targeting genomic pathways altered in these patients, leading to promising responses. These agents act by inhibiting poly-ADP ribose polymerase (PARP) enzymes involved in repairing single-strand breaks in the DNA. Based on the PROfound and TRITON3 trials, olaparib and rucaparib were respectively approved as monotherapy in pretreated patients with mCRPC and alterations in prespecified genes. The combinations of olaparib with abiraterone (PROpel) and niraparib with abiraterone (MAGNITUDE) were approved as first-line options in patients with mCRPC and alterations in <i>BRCA1/2</i>, whereas the combination of talazoparib with enzalutamide (TALAPRO-2) was approved in the same setting in patients with alterations in any of the HRR genes, which are found in around a quarter of patients with advanced prostate cancer. Additional trials are already underway to assess these agents in an earlier hormone-sensitive setting. Future directions will include refining the treatment sequencing in patients with mCRPC in the clinic while taking into account the financial toxicity as well as the potential side effects encountered with these therapies and elucidating their mechanism of action in patients with non-altered HRR genes. Herein, we review the biological rationale behind using PARPis in mCRPC and the key aforementioned clinical trials that paved the way for these approvals.https://www.mdpi.com/2075-1729/14/2/198metastatic prostate cancerpoly-ADP ribose polymerase inhibitorsBRCAHRR |
| spellingShingle | Ashaar Al-Akhras Chadi Hage Chehade Arshit Narang Umang Swami PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Unraveling the Therapeutic Landscape Life metastatic prostate cancer poly-ADP ribose polymerase inhibitors BRCA HRR |
| title | PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Unraveling the Therapeutic Landscape |
| title_full | PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Unraveling the Therapeutic Landscape |
| title_fullStr | PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Unraveling the Therapeutic Landscape |
| title_full_unstemmed | PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Unraveling the Therapeutic Landscape |
| title_short | PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Unraveling the Therapeutic Landscape |
| title_sort | parp inhibitors in metastatic castration resistant prostate cancer unraveling the therapeutic landscape |
| topic | metastatic prostate cancer poly-ADP ribose polymerase inhibitors BRCA HRR |
| url | https://www.mdpi.com/2075-1729/14/2/198 |
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