Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors, such as olaparib, talazoparib, rucaparib, and niraparib, comprise a therapeutic class that targets PARP proteins involved in DNA repair. Cancer cells with homologous recombination repair defects, particularly BRCA alterations, display enhanced sensitivity to these agents because of synthetic lethality induced by PARP inhibitors. These agents have significantly improved survival outcomes across various malignancies, initially gaining regulatory approval in ovarian cancer and subsequently in breast, pancreatic, and prostate cancers in different indications. This review offers a comprehensive clinical overview of PARP inhibitor approvals, emphasizing their efficacy across different cancers based on landmark phase 3 clinical trials.

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 BRCA1/2, 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.

Summary: To date, immune targeting agents have provided limited benefits in patients with metastatic prostate cancer. Bispecific T-cell engagers, especially targeting STEAP1, have shown encouraging results in preclinical and phase I studies and thus represent a novel and promising treatment option in this setting. See related article by Nolan-Stevaux et al., p. 90 (7). See related article by Kelly et al., p. 76 (8).

Purpose: Immune checkpoint inhibitors (ICI) have shown limited efficacy in unselected patients with metastatic castration-resistant prostate cancer (mCRPC). However, ICIs are approved for biomarker-defined subsets: microsatellite instability–high (MSI-H) and/or high tumor mutational burden (TMB-H). The efficacy of ICIs in TMB-H but not MSI-H disease remains unclear, and limited data exist evaluating ICI outcomes associated with blood-based MSI (bMSI) in mCRPC. Experimental Design: This study used the United States–based deidentified Flatiron Health–Foundation Medicine prostate cancer Clinico-Genomic Database. Patients with tissue-assessed MSI (tMSI) and TMB (tTMB) status by an algorithm supporting an FDA-approved CDx for pembrolizumab were included if treated with single-agent ICI. Separately, outcomes on ICI associated with bMSI were assessed, including if treated with single-agent ICI or taxane. Results: Among 2,965 patients with mCRPC, tMSI-H (3.2%) was nearly always also tTMB ≥10 mut/Mb (4.7%). In 84 ICI-treated patients, time to next treatment (TTNT) and overall survival (OS) were more favorable in tMSI-H with any TMB [TTNT HR, 0.18; 95% confidence interval (CI), 0.09–0.37 and OS HR, 0.32; 95% CI, 0.15–0.66] and tTMB ≥10 without tMSI-H (TTNT HR, 0.18; 95% CI, 0.04–0.48 and OS HR, 0.20; 95% CI, 0.05–0.77) compared with tTMB <10 without tMSI-H group. In intrapatient assessments, patients with tTMB ≥10 had more favorable TTNT with subsequent ICI versus prior taxane. Detection of bMSI-H was associated with more favorable TTNT on ICI (HR, 0.34; 95% CI, 0.14–0.83) and OS (HR, 0.21; 95% CI, 0.06–0.75) when tumor fraction ≥1%. Conclusions: These findings add support for tTMB and tMSI in predicting ICI monotherapy benefit in mCRPC and provide evidence supporting bMSI testing when tissue is unavailable.

Ipilimumab with nivolumab (Ipi + Nivo) and immune checkpoint inhibitors with tyrosine kinase inhibitors (ICI + TKI) are the first-line approved treatments for intermediate- and poor-risk metastatic clear cell renal cell carcinoma (mccRCC); however, they have not been compared head-to-head in prospective trials to guide treatment selection. Thereupon, we sought to compare survival outcomes of patients receiving first-line Ipi + Nivo versus ICI + TKI, using a large, real-world database among patients with intermediate- and poor-risk mccRCC. This retrospective cohort study used a nationwide electronic health record-derived deidentified database, where patients with mccRCC with intermediate- or poor-risk who received first-line Ipi + Nivo or ICI + TKI between 20 June, 2016, and 26 January, 2023, were included. Primary outcomes were real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS), summarized via Kaplan-Meier survival estimates with 95% confidence intervals (CIs) and compared in the context of propensity score (PS) matching weighted analysis. Of the 12,707 patients in the dataset, 1,438 with mccRCC met eligibility and were included. After PS matching weighted analysis, no significant difference in rwOS was noted between both groups (HR 1.01, 95% CI 0.86–1.19; p = 0.91); however, rwTTNT was significantly shorter with Ipi + Nivo than with ICI + TKI (HR 0.78, 95% CI 0.68–0.89; p < 0.001). In this large real-world study, there was evidence that rwOS was comparable, while rwTTNT was superior in patients receiving ICI + TKI compared to those receiving Ipi + Nivo. These real-world data offer important guidance for clinicians in choosing between Ipi + Nivo and ICI + TKI as frontline treatment.