Clinical Application of Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Prostate Cancer

Abstract

Approximately a quarter of men with metastatic castrate resistant prostate cancer (mCRPC) have alterations in homologous recombination repair (HRR). These patients exhibit enhanced sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Leveraging the synthetic lethality between PARP inhibition and HRR deficiency, studies have established marked clinical benefit and a survival advantage from PARP inhibitors (PARPi) in mCRPC, most notably in cancers with BRCA1/2 alterations. The role of PARPi is evolving beyond patients with HRR alterations, with studies increasingly focused on exploiting synergistic effects from combination therapeutics. Strategies combining PARP inhibitors with androgen receptor pathway inhibitors, radiation, radioligand therapy, chemotherapy and immunotherapy demonstrate potential additional benefits in mCRPC and these approaches are rapidly moving into the metastatic hormone sensitive treatment paradigm. In this review we summarise the development and expanding role of PARPi in prostate cancer including biomarkers of response, the relationship between the androgen receptor and PARP, evidence for combination therapeutics and the future directions of PARPi in precision medicine for prostate cancer.

PARP Inhibitors for Metastatic Urothelial Carcinoma: A Systematic Review of Efficacy and Safety

“…This resulted in gene lists that, whilst similar, were not identical. This parallels circumstances in other cancers where optimal biomarker composition remains to be fully defined, such as in prostate cancer [11]. One consequence, that seems likely to be replicated in MUC, is that the individual relevance for each incorporated gene, at least beyond BRCA1 and BRCA2, may be challenging, if not impossible to determine.…”

“…Relevant genes include, BRCA1, BRCA2, ATM, RB1, PALB2, FANCC, FANCD2, and ERCC2. This raises the potential for a therapeutic vulnerability towards agents that interfere with DNA damage repair, of which the furthest developed are poly (ADP-ribose) polymerase (PARP) inhibitors [11][12][13]. MUC pre-clinical models are sensitive to PARP inhibition, and there is phenotypic overlap with gene alteration patterns that are known to predict for responsiveness to platinum based chemotherapy [14][15][16][17][18][19][20].…”

“…PARP inhibition is a standard of care approach in a variety of cancers including breast cancer, ovarian cancer and prostate cancer [11][12][13]. Across these diseases, there exist a multitude of treatment strategies, including monotherapy, combination or sequencing with platinum based chemotherapy or combination with other treatment modalities such as immunotherapy.…”

Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis

“…The taxanes docetaxel and cabazitaxel are approved for late-stage prostate cancer, and the combination of docetaxel with androgen deprivation therapy and the AR inhibitor darolutamide has recently been shown to have superior clinical benefits [7,8]. Two poly(ADP-ribose) polymerase (PARP) inhibitors are used to treat men with mCRPC harboring alterations in homologous recombination repair genes [9]. Combination studies of PARP inhibitors with different AR signaling inhibitors are currently being clinically assessed [9].…”

“…Two poly(ADP‐ribose) polymerase (PARP) inhibitors are used to treat men with mCRPC harboring alterations in homologous recombination repair genes [9]. Combination studies of PARP inhibitors with different AR signaling inhibitors are currently being clinically assessed [9]. The α‐emitter radium‐223 is approved for mCRPC patients with bone metastases, but no visceral involvement [10], and the cotreatment with the AR inhibitor enzalutamide is being evaluated in the clinic [11].…”