Precision Medicine in Castration-Resistant Prostate Cancer: Advances, Challenges, and the Landscape of PARPi Therapy - A Narrative Review

Q: PARPi use differs how in mCRPC compared with breast or ovarian cancer?

In mCRPC, PARPis are applied to a broader spectrum of genetic aberrations rather than being limited only to BRCA1/2 alterations, as described for breast or ovarian cancer approvals.

Q: What evidence suggests PARPi accessibility may expand in mCRPC?

Key findings from the phase III PROPEL trial indicate that PARPis’ accessibility may broaden even without mandatory testing.

Q: Why is therapy resistance an important issue with PARPi treatment?

Although PARPis can be initially effective in BRCA-mutated tumors, resistance frequently occurs, making biomarker-based patient stratification important for optimizing benefits and minimizing toxicity.

Sep 22, 2026

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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 restricted use in breast or ovarian cancer limited to BRCA1/2 alterations, PARPis in mCRPC are used across a broader spectrum of genetic aberrations. Phase III PROPEL trial results suggest expanded accessibility even without mandatory testing. Biomarker-driven evidence highlights homologous recombination repair (HRR) gene alterations and distinct PARPi sensitivities. Despite initial benefits in BRCAmutated tumors, resistance is common, supporting patient stratification by biomarkers and genetic signatures to refine first-line PARPi efficacy while addressing toxicity.

LanguageEnglish

CategoryHealthcare

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Abstract

Introduction

DNA Damage Repair Mechanisms

Review Precision Medicine in Castration-Resistant Prostate Cancer: Advances, Challenges, and the Landscape of PARPi Therapy—A Narrative Review George Dimitrov 1, Radoslav Mangaldzhiev 1, Chavdar Slavov 2 and Elenko Popov 2, * Citation: Dimitrov, G.; Mangaldzhiev, R.; Slavov, C.; Popov, E. Precision Medicine in Castration-Resistant Prostate Cancer: Advances, Challenges, and the Landscape of PARPi Therapy—A Narrative Review. Int. J. Mol. Sci. 2024, 25, 2184. [https://](https://)[ ](https://)[doi.org/10.3390/ijms25042184](doi.org/10.3390/ijms25042184) Academic Editor: Francesca Sanguedolce Received: 13 January 2024 Revised: 8 February 2024 Accepted: 10 February 2024 Published: 11 February 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Medical Oncology, Medical University of Sofia, University Hospital “Tsaritsa Yoanna”, 1527 Sofia, Bulgaria; gdimitrov@medfac.mu-sofia.bg (G.D.) 2 Department of Urology, Medical University of Sofia, University Hospital “Tsaritsa Yoanna”, 1527 Sofia, Bulgaria; [ch.k.slavov@gmail.com](ch.k.slavov@gmail.com) * [Correspondence: e.popov@medfac.mu-sofia.bg](Correspondence: e.popov@medfac.mu-sofia.bg); Tel.: +359-889428586 Abstract: 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 BRCAmutated 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. Keywords: PARPi; mCRPC; HRR genes; BRCA1/2 alterations; personalized medicine 1. Introduction Castration-resistant prostate cancer (CRPC), defined by castrate serum testosterone levels (<50 ng/dL or 1.7 nmol/L) coupled with biochemical or radiological progression per the European Association of Urology’s guidelines [1], manifests as a clinically diverse entity marked by heightened mortality [2] . Despite recent therapeutic advances, the landscape of metastatic (m)CRPC treatment has undergone a significant evolution, ushering in a new era of possibilities. In the current paradigm, first-line treatments for mCRPC primarily center around androgen receptor signaling inhibitors (ARSis) (e.g., abiraterone acetate and enzalutamide) meticulously crafted to thwart the reactivation of the androgen receptor (AR) signaling pathway [3,4] . Simultaneously, taxane-based chemotherapy (docetaxel and cabazitaxel) alongside androgen deprivation therapy [5] serves as a viable strategy [6,7] . Moreover, the benefits of non-drug-based therapeutic modalities, such as immunotherapy with SipuleucelT and nuclear medicine approaches exemplified by radium-223, have been demonstrated in this context [8,9] . These strategies aim not only to impede disease progression, but also to enhance overall patient outcomes [10] . Amidst this dynamic landscape, the integration of poly-adenosine diphosphate [ADP]-ribose polymerase inhibitors (PARPis) conc

FAQs

PARPi use differs how in mCRPC compared with breast or ovarian cancer?

In mCRPC, PARPis are applied to a broader spectrum of genetic aberrations rather than being limited only to BRCA1/2 alterations, as described for breast or ovarian cancer approvals.

What evidence suggests PARPi accessibility may expand in mCRPC?

Key findings from the phase III PROPEL trial indicate that PARPis’ accessibility may broaden even without mandatory testing.

Why is therapy resistance an important issue with PARPi treatment?

Although PARPis can be initially effective in BRCA-mutated tumors, resistance frequently occurs, making biomarker-based patient stratification important for optimizing benefits and minimizing toxicity.

Sep 22, 2026

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