Poly (ADP-ribose) polymerase inhibitor: A new horizon in advanced prostate cancer treatment

While prostate cancer (PCa) has been regarded as a single entity with a largely uniform approach to management over the last few decades, recent advancements in the molecular biology and genomics of PCa have shed light on the extensive inter- and intratumor heterogeneities [1]. Consequently, PCa is no more considered a uniform disease but a spectrum of diseases with unique genetic and molecular profiles. This highlights the need for novel therapeutic strategies to manage and treat this complex disease effectively. Moreover, this evolution in the understanding of PCa biology has paved the way for an era of precision medicine that has led to the identification of specific genetic alterations that play key roles in disease progression and response to therapy [2]. Mutations in homologous recombination repair (HRR) genes have attracted significant attention owing to the clinical implications of poly (ADP-ribose) polymerase (PARP) inhibitors. HRR is a DNA repair mechanism of cells fixing double-strand breaks using a DNA template, and loss of function of HRR can accumulate genomic instability in the cells. Herein, we aim to discuss the advent of PARP inhibitors, a class of drugs that have emerged at the forefront of precision medicine in advanced PCa, and their implications for future management strategies.

Recent studies have shown that approximately 20%–30% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in these HRR genes, which is significantly higher than that in localized PCa [3]. These mutations exhibit important clinical implications. In particular, HRR mutations have been associated with increased sensitivity to therapies that cause DNA damage, such as platinum-based chemotherapy and PARP inhibitors [3]. In cancer cells harboring HRR mutations, PARP inhibitors cause lethal accumulation of DNA damage, effectively inducing cell death, a concept referred to as synthetic lethality [4]. Simply, synthetic lethality refers to a condition where mutations in two genes together cause cell death, while a mutation in each gene alone does not. This principle is used in cancer therapy to target cells with specific genetic vulnerabilities. Importantly, significant developments in the field have led to the discovery of the interplay between androgen receptor (AR) signaling, which is the androgen-activated pathway controlling genes associated with cell growth, particularly critical in PCa progression, and DNA repair processes. The simultaneous inhibition of PARP and AR signaling exerts a synergistic effect by which PARP inhibitors downregulate AR transcriptional activity. AR-targeting agents can disrupt the repair of single-stranded breaks, which enhances the sensitivity of cancer cells to DNA-damaging agents, such as PARP inhibitors [4]. This potential synergy forms the basis for the design of several clinical trials investigating the combination of PARP inhibitors and AR-targeting agents for the treatment of mCRPC.

A series of pivotal clinical trials have underscored the potential of PARP inhibitors in PCa therapy. The PROFOUND study demonstrated the efficacy of the PARP inhibitor olaparib in men with mCRPC harboring specific HRR gene alterations and whose disease had progressed during previous treatment with novel AR-targeting agents [5]. In this trial, the patients were categorized into two cohorts. Cohort A included patients with alterations in BRCA1, BRCA2, or ATM genes, which are considered to have a direct and significant role in the HRR pathway. Cohort B comprised patients with alterations in any of the other 12 HRR-related genes that were included in the study. The trial demonstrated the effectiveness of olaparib in both cohorts; however, the results were particularly striking in Cohort A [5]. In this group, olaparib significantly improved radiographic progression-free survival (r-PFS) compared to the control arm, in which patients received novel AR-targeting agents (either enzalutamide or abiraterone acetate) [5]. Moreover, olaparib was beneficial in terms of overall survival (OS), particularly in Cohort A; however, this benefit was less pronounced in Cohort B [5]. This underlines the importance of identifying patients with mutations in BRCA1, BRCA2, and ATM as they seem to derive the greatest benefit from treatment with PARP inhibitors. This differential response based on the type of HRR gene alteration underscores the necessity for comprehensive genetic profiling of patients with mCRPC to help guide personalized treatment strategies. This also highlights the need for continued research to further understand the complex interplay between different HRR gene alterations and responses to PARP inhibitors. These results established olaparib as a standard of care for patients with mCRPC harboring specific HRR gene alterations who underwent prior treatment with AR-targeting agents, marking a significant step forward in the field of precision medicine for PCa.

Subsequently, three phase III studies (PROpel, TALAPRO-2, and MAGNITUDE) were conducted, which provided compelling evidence supporting the combination therapy of PARP inhibitors and novel AR-targeting agents as the first-line therapy at the mCRPC stage [6, 7, 8]. In the PROpel study, abiraterone acetate and prednisolone (AAP) and olaparib combination therapy successfully improved r-PFS compared to those in the AAP and placebo arm (24.8 vs. 16.6 mo; hazard ratio [HR]=0.66; 95% confidence interval [CI]=0.54–0.81), particularly regardless of HRR gene mutation status [6]. The TALAPRO-2 trial also showed that r-PFS was significantly longer in the talazoparib/enzalutamide group than that in the enzalutamide/placebo group (not reached [NR] vs. 21.9 mo; HR=0.63; 95% CI=0.51–0.78) [7]. Although the PROpel and TALAPRO-2 trials were conducted in an all-comer setting, the benefits of r-PFS were primarily observed in patients with mCRPC with HRR gene aberrations [6, 7]. The MAGNITUDE trial was performed in mCRPC patients harboring at least one of nine common HRR gene mutations [8]. This study confirmed that niraparib with AAP significantly reduced the risk of progression or death, compared to those treated by AAP with placebo, particularly in patients harboring BRCA1/BRCA2 gene aberration (HR=0.53, 95% CI=0.36–0.79) [8].

Despite the promising rPFS data in these trials, no notable benefits of PARP inhibitors and AR-targeting agent combinations in terms of OS outcomes were observed. A recent update of the PROpel trial showed a trend towards an OS rate that was not statistically significant (42. 1 vs. 34.7 mo; HR=0.81; 95% CI=0.67–1.00) for all comers at data maturity of 47.9% [9]. Interestingly, patients with BRCA1/2 aberrations had significantly better OS outcomes in the AAP/olaparib arm compared to those in the AAP/placebo arm (NR vs. 23 mo; HR=0.29; 95% CI=0.14–0.56), suggesting that the survival benefit trend in the whole population was mainly derived by patients who had BRCA1/2 gene aberrations [9]. Thus, it is pertinent to allow sufficient time for the mature final OS data of the PROpel, TALAPRO-2, and MAGNITUDE trials to be updated, particularly for patients without HRR gene alterations. This will enable a comprehensive understanding of the benefits of combination therapy, particularly considering the potential side effects and the ways in which these treatments will impact the quality of life.

The future direction of PARP inhibitors in PCa treatment is multifaceted and encompasses several aspects, including the identification of predictive biomarkers and optimization of combination strategies. Moreover, the optimal sequencing algorithm for PARP and other therapeutic modalities, including AR-targeting agents and chemotherapy, remains to be determined. The aforementioned clinical trials have provided promising results in this area; however, further research is needed to determine the optimal sequencing of these agents to achieve the best outcomes for patients. Four different clinical scenarios can be considered [10]. First, for the treatment of mHSPC with ADT alone, patients harboring HRR gene mutations should be recommended either AAP/olaparib or enzalutamide/talazoparib as the first-line treatment option for mCRPC. Conversely, in the absence of HRR mutations, combination therapy with AAP/olaparib or enzalutamide/talazoparib can be proposed as the first-line treatment strategy. In the subsequent stages of treatment, Docetaxel or Radium-223 may be considered as the second-line treatment option, whereas cabazitaxel or ¹⁷⁷Lu-PSMA could be proposed as the potential third-line therapeutic option, irrespective of the HRR mutation status. Second, for ADT plus early docetaxel treatment in mHSPC, patients with HRR gene mutations could be recommended treatment with either AAP/olaparib or enzalutamide/talazoparib as the first-line treatment option, and ¹⁷⁷Lu-PSMA, cabazitaxel or Radium-223 could be suggested as the second-line therapeutic strategy for mCRPC, regardless of the HRR mutation status. Third, in the case of mHSPC treated with ADT plus AR-targeting agents, patients with HRR gene mutations, particularly BRCA1/2 genes, could be recommended treatment with olaparib, rucaparib, or docetaxel as the first-line treatment option for mCRPC. Conversely, in patients with non-HRR gene (particularly BRCA1/2) mutations, docetaxel or Radium-223 could be suggested as the first-line treatment option for mCRPC. Finally, triplet therapy with ADT plus docetaxel and AR-targeting agents in mHSPC and patients with HRR gene mutations, including BRCA1/2 genes, could be treated with olaparib or rucaparib as the first-line treatment option, and ¹⁷⁷Lu-PSMA, cabazitaxel or Radium-223 may be considered as the second-line therapeutic modalities in mCRPC. However, for patients without HRR gene mutations, ¹⁷⁷Lu-PSMA, cabazitaxel or Radium-223 may be suggested as the first-line treatment option for mCRPC. As our understanding of this complex disease continues to evolve, we can optimize the use of these agents and improve their efficacy in real-world practice.

In conclusion, PARP inhibitors, either as monotherapy or in combination with AR-targeting agents, show significant promise for the treatment of mCRPC even in the first-line setting. As our understanding continues to refine the genetic and molecular underpinnings of this complex disease with genomic heterogeneity, we expect the landscape of advanced PCa treatment to evolve accordingly, offering a new horizon in advanced PCa treatment with PARP inhibitor combinations.