Genomic landscape of liquid biopsy mutations in TP53 and DNA damage genes in cancer patients.

Next-generation sequencing (NGS) assays based on plasma cell-free DNA (cfDNA) are increasingly used for clinical trials inclusion. Their optimized limit of detection applied to a large number of genes leads to the identification of mutations not confirmed in tissue. It becomes essential to describe the characteristics and consequences of these liquid biopsy-only mutations. In the STING protocol (Gustave Roussy, NCT04932525), 542 patients with advanced solid cancer had cfDNA-based and tissue-based NGS analysis (performed by FoundationOne® Liquid CDx and FoundationOne CDx™, respectively). Mutations identified in the liquid biopsy but not in the paired tissue were considered as liquid biopsy-only mutations irrespective of their variant allelic frequency (VAF). Out of 542 patients, 281 (51.8%) harbored at least one liquid biopsy-only mutation. These patients were significantly older, and more heavily pretreated. Liquid biopsy-only mutations occurring in TP53, and in DDR genes (ATM, CHEK2, ATR, BRCA2, and BRCA1) accounted for 90.8% of all the mutations. The median VAF of these mutations was generally low (0.37% and 0.40% for TP53 and DDR genes respectively). The variant type repartition depended on the gene. Liquid biopsy-only mutations affected hotspot in TP53 codon 273, 125, 195, 176, 237 or 280 and ATM codon 2891 and 3008. In a subset of 37 patients, 75.0%, 53.5% and 83.3% of the liquid biopsy-only mutations occurring respectively in ATM, TP53, and CHEK2 were confirmed in the matching whole blood sample. Although liquid biopsy-only mutations makes the interpretation of liquid biopsy results more complex, they have distinct characteristics making them more easily identifiable.

Resistance to BRAF inhibition explored through single circulating tumour cell molecular profiling in BRAF-mutant non-small-cell lung cancer.

BACKGROUND: Resistance mechanisms to combination therapy with dabrafenib plus trametinib remain poorly understood in patients with BRAFV600E-mutant advanced non-small-cell lung cancer (NSCLC). We examined resistance to BRAF inhibition by single CTC sequencing in BRAFV600E-mutant NSCLC. METHODS: CTCs and cfDNA were examined in seven BRAFV600E-mutant NSCLC patients at failure to treatment. Matched tumour tissue was available for four patients. Single CTCs were isolated by fluorescence-activated cell sorting following enrichment and immunofluorescence (Hoechst 33342/CD45/pan-cytokeratins) and sequenced for mutation and copy number-alteration (CNA) analyses. RESULTS: BRAFV600E was found in 4/4 tumour biopsies and 5/7 cfDNA samples. CTC mutations were mostly found in MAPK-independent pathways and only 1/26 CTCs were BRAFV600E mutated. CTC profiles encompassed the majority of matched tumour biopsy CNAs but 72.5% to 84.5% of CTC CNAs were exclusive to CTCs. Extensive diversity, involving MAPK, MAPK-related, cell cycle, DNA repair and immune response pathways, was observed in CTCs and missed by analyses on tumour biopsies and cfDNA. Driver alterations in clinically relevant genes were recurrent in CTCs. CONCLUSIONS: Resistance was not driven by BRAFV600E-mutant CTCs. Extensive tumour genomic heterogeneity was found in CTCs compared to tumour biopsies and cfDNA at failure to BRAF inhibition, in BRAFV600E-mutant NSCLC, including relevant alterations that may represent potential treatment opportunities.

Meta-Analysis on the Combination of Chemotherapy With Programmed Death-Ligand 1 and Programmed Cell Death Protein 1 Blockade as First-Line Treatment for Unresectable Pleural Mesothelioma.

INTRODUCTION: Dual immune checkpoint blockers regimen represents a standard first-line therapy in unresectable pleural mesothelioma (PM). Novel combination strategies, including immune checkpoint blockers and antiangiogenic drugs, are currently under investigation in this setting. We aimed to assess the efficacy of the chemoimmunotherapy combination by reference to literature evidence. METHODS: A systematic review and meta-analysis of trials with first-line platinum-based chemotherapy associated with programmed death-ligand 1 and programmed cell death protein 1 agent in unresectable PM. We estimated the weighted summary proportion of disease response, along with the landmark probability of survival outcomes. RESULTS: A total of 349 patients with unresectable PM from four trials (DREAM, PrE0505, JME-001, and IND.227) were included, 79% (n = 274) with epithelioid and 21% (n = 75) with nonepithelioid histologic type. In aggregate, the objective response rate was 59.2% (95% confidence interval [CI]: 50.3%-67.9%) and disease control rate was 92.2% (95% CI: 89.2%-94.8%). Comparing epithelioid versus nonepithelioid tumors, the objective response rate was 64.5% versus 46.4%, (p < 0.001) and the disease control rate was 92.3% versus 80.0%, (p = 0.043), with an OR of 2.56 (95% CI: 1.51-4.32) for disease response and of 3.37 (95% CI: 0.99-11.47) for disease control. The aggregated estimated probability of progression-free survival was 63% (95% CI: 53%-71%) at 6 months and 25% (95% CI: 21%-31%) at 12 months, whereas the 6-, 12- and 24-month overall survival rates were 88% (95% CI: 81%-93%), 71% (95% CI: 61%-79%) and 39% (95% CI: 34%-45%), respectively. CONCLUSIONS: According to our analysis, first-line chemoimmunotherapy holds promise as a new treatment approach for PM, exhibiting encouraging survival outcomes and an enhanced response rate, including for the epithelioid subtype. Ongoing studies are necessary to establish its precise placement within the treatment algorithm.

Olaparib maintenance versus placebo in platinum-sensitive non-small cell lung cancer: the Phase 2 randomized PIPSeN trial.

BACKGROUND: Platinum-sensitivity is a phenotypic biomarker of Poly (ADP-ribose) polymerase inhibitors (PARPi) sensitivity in histotypes where PARPi are approved. Approximately one-third of non-small cell lung cancers (NSCLC) are platinum-sensitive. The double-blind, randomized phase II PIPSeN (NCT02679963) study evaluated olaparib, a PARPi, as maintenance therapy for patients with platinum-sensitive advanced NSCLC. METHODS: Chemonaïve patients with ECOG performance status of 0-1, platinum-sensitive, EGFR- and ALK-wild-type, stage IIIB-IV NSCLC were randomized (R) to receive either olaparib (O) maintenance or a placebo (P). The primary objective was progression-free survival (PFS) from R. Secondary objectives included overall survival (OS) and safety. With an anticipated hazard ratio of 0.65, 144 patients were required to be randomized, and approximately 500 patients enrolled. RESULTS: The trial was prematurely terminated because anti-PD(L)1 therapy was approved during the trial recruitment. A total of 182 patients were enrolled, with 60 patients randomized: 33 and 27 in the O and P arms, respectively. Patient and tumor characteristics were well-balanced between arms, except for alcohol intake (33% vs 11% in the O and P arms, respectively, p = 0.043). The median PFS was 2.9 and 2.0 months in the O and P arms, respectively (logrank p = 0.99). The median OS was 9.4 and 9.5 months in the O and P arms, respectively (p = 0.28). Grade ≥3 toxicities occurred in 15 and 8 patients in O and P arms, with no new safety concerns. CONCLUSION: PIPSeN was terminated early after enrollment of only 50% of the pre-planned population, thus being statistically underpowered. Olaparib maintenance did neither improve median PFS nor OS in this patient population.

Patterns of Treatment Failure After Selective Rearranged During Transfection (RET) Inhibitors in Patients With Metastatic Medullary Thyroid Carcinoma.

PURPOSE: Medullary thyroid cancer (MTC) harbors frequent mutations in RET oncogene. Selective RET inhibitors (RETi) have emerged as effective treatments. However, resistance almost invariably occurs. METHODS: MTC patients who were initiated on RETi between 2018 and 2022 were included. Baseline characteristics, RET mutational status, RETi response, available tumor tissue and molecular profiles sampled pre- and post-RETi were analyzed. RESULTS: Among 46 MTC patients on RETi during the study period, 26 patients had discontinued at data cut-off because of progression (n = 16), death (n = 4), and toxicity (n = 6). The most frequent RET mutations at baseline were p.M918T (n = 29), and p.C634X (n = 6). Pre- and post-RETi molecular profiles were available in 14 patients. There was no primary resistance on pre-RETi samples. Post-RETi profiles revealed a bypass mechanism of resistance in 75% of the cases including RAS genes mutations (50%), FGFR2 and ALK fusions and and MYC p.P44L. RET solvent from and hinge region mutations was the only resistance mechanisms in 25% of the cases. Tumor samples from initial thyroidectomy, pre- and post-RETi, from six patients, showed an increase of the mean Ki 67-index of 7%, 17% and 40% respectively (P = 0.037) and a more aggressive poorly differentiated histology in three patients. DISCUSSION: Bypass resistance may be the most frequent mechanism of progression under RETi. A more aggressive histology may arise following RETi and warrants further investigation.

Circulating tumor DNA landscape and prognostic impact of acquired resistance to targeted therapies in cancer patients: a national center for precision medicine (PRISM) study.

BACKGROUND: Despite the effectiveness of the various targeted therapies currently approved for solid tumors, acquired resistance remains a persistent problem that limits the ultimate effectiveness of these treatments. Polyclonal resistance to targeted therapy has been described in multiple solid tumors through high-throughput analysis of multiple tumor tissue samples from a single patient. However, biopsies at the time of acquired resistance to targeted agents may not always be feasible and may not capture the genetic heterogeneity that could exist within a patient. METHODS: We analyzed circulating tumor DNA (ctDNA) with a large next-generation sequencing panel to characterize the landscape of secondary resistance mechanisms in two independent prospective cohorts of patients (STING: n = 626; BIP: n = 437) with solid tumors who were treated with various types of targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies and hormonal therapies. RESULTS: Emerging alterations involved in secondary resistance were observed in the plasma of up 34% of patients regardless of the type of targeted therapy. Alterations were polyclonal in up to 14% of patients. Emerging ctDNA alterations were associated with significantly shorter overall survival for patients with some tumor types. CONCLUSION: This comprehensive landscape of genomic aberrations indicates that genetic alterations involved in secondary resistance to targeted therapy occur frequently and suggests that the detection of such alterations before disease progression may guide personalized treatment and improve patient outcome.

Prevalence of Thromboembolic Events in Patients With Non-Small Cell Lung Cancer and RET Fusions.

This cohort study examines the incidence, risks, and characteristics of deep vein thrombosis, pulmonary embolism, arterial thrombosis, and stroke among patients with non­small cell lung cancer (NSCLC) and RET fusions.

Stereotactic body radiotherapy for extra-cranial oligoprogressive or oligorecurrent small-cell lung cancer.

Introduction: The role of local ablative treatments, including stereotactic body radiotherapy (SBRT), is an area of active research in oligometastatic patients. Small cell lung cancer (SCLC) has a poor prognosis, with common diffuse metastatic evolution. We evaluated the outcomes after SBRT in uncommon oligoprogressive/oligorecurrent SCLC presentation. Methods: Data of SCLC patients who received SBRT for oligoprogressive/oligorecurrent metastatic disease at four centers were retrospectively analyzed. Patients with synchronous oligometastatic disease, SBRT for primary lung tumor and brain radiosurgery were not included. Relapse and survival rates were defined as the time between the date of SBRT and the first event. Results: Twenty patients (60% with initially limited-disease [LD]) presenting 24 lesions were identified. Oligoprogression and oligorecurrence were observed in 6/20 (30%) and 14/20 (70%) patients, respectively. SBRT was delivered to one (n = 16) to two (n = 4) lesions (median size, 26 mm), mainly to lung [n = 17/24] metastases. At a median follow-up of 2.9 years, no local relapse was observed and 15/20 patients experienced a distant relapse (DR). The median DR and OS were 4.5 months (95 %CI: 2.9-13.7 months) and 17.2 months (95 %CI: 7.5-65.2 months), respectively. The 3-year distant control and OS rates were 25% (95 %CI: 6-44%) and 37% (95 %CI: 15-59%), respectively. Initial LD (vs extensive-disease) was the only prognosis factor associated with a lower risk of post-SBRT DR (HR: 0.3; 95% CI: 0-0.88; p = 0.03). There was no severe observed SBRT-related toxicities. Conclusion: Prognosis was poor, with DR occurring in most patients. However, local control was excellent and long term response after SBRT may rarely occur in patients with oligoprogressive/oligorecurrent SCLC. Local ablative treatments should be discussed in a multidisciplinary setting on well-selected cases.

Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC.

Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. SIGNIFICANCE: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501.

Liquid Biopsies for Circulating Tumor DNA Detection May Reveal Occult Hematologic Malignancies in Patients With Solid Tumors.

PURPOSE: High-risk clonal hematopoiesis (CH) is frequently incidentally found in patients with solid tumors undergoing plasma cell-free DNA sequencing. Here, we aimed to determine if the incidental detection of high-risk CH by liquid biopsy may reveal occult hematologic malignancies in patients with solid tumors. MATERIALS AND METHODS: Adult patients with advanced solid cancers enrolled in the Gustave Roussy Cancer Profiling study (ClinicalTrials.gov identifier: NCT04932525) underwent at least one liquid biopsy (FoundationOne Liquid CDx). Molecular reports were discussed within the Gustave Roussy Molecular Tumor Board (MTB). Potential CH alterations were observed, and patients referred to hematology consultation in the case of pathogenic mutations in JAK2, MPL, or MYD88, irrespective of the variant allele frequency (VAF), or in DNMT3A, TET2, ASXL1, IDH1, IDH2, SF3B1, or U2AF1 with VAF ≥ 10%, while also considering patient cancer-related prognosis. TP53 mutations were discussed case-by-case. RESULTS: Between March and October 2021, 1,416 patients were included. One hundred ten patients (7.7%) carried at least one high-risk CH mutation: DNMT3A (n = 32), JAK2 (n = 28), TET2 (n = 19), ASXL1 (n = 18), SF3B1 (n = 5), IDH1 (n = 4), IDH2 (n = 3), MPL (n = 3), and U2AF1 (n = 2). The MTB advised for hematologic consultation in 45 patients. Overall, 9 patients of 18 actually addressed had confirmed hematologic malignancies that were occult in six patients: two patients had myelodysplastic syndrome, two essential thrombocythemia, one a marginal lymphoma, and one a Waldenström macroglobulinemia. The other three patients were already followed up in hematology. CONCLUSION: The incidental findings of high-risk CH through liquid biopsy may trigger diagnostic hematologic tests and reveal an occult hematologic malignancy. Patients should have a multidisciplinary case-by-case evaluation.

Clinical outcomes by infusion timing of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.

BACKGROUND: We aimed to determine whether immune checkpoint inhibitors (ICI) time-of-day infusion might influence the survival of patients with advanced non-small cell lung cancer (NSCLC). METHODS: We retrospectively analysed patients who received single-agent anti-PD-(L)1 therapy in any line between 2016 and 2021. We calculated by Cox regression models the association between the proportion of ICI infusions received after 16:30h and overall survival (OS) and progression-free survival (PFS). RESULTS: 180 patients were included, 77% received ICI as second- or further-line (median of 12 infusions/patient). The median age was 65 years (IQR 57-70), 112 patients (62%) were male, 165 (92%) were current or former tobacco smokers, 140 (78%) had performance status (PS) 0 or 1, 26 (14%) were on steroid therapy at ICI initiation. Histology was non-squamous for 139 (77%), the median number of metastatic sites was 3, and 33% had brain metastases. Patients who received at least 20% of ICI infusions after 16:30h (65 out of 180, 36%) had a statistically significant shorter median PFS as compared with patients receiving less than 20% of infusions in the evening (4.9 vs 9.4 months, log-rank p = 0.020), while numerical but not statistical shorter OS was observed (14.0 vs 26.2 months, log-rank p = 0.090). In the multivariate analysis, receiving at least 20% of evening infusions did not significantly increase the risk of death, while PS and line of treatment were significantly correlated with the OS. On the contrary, a proportion of ICI administration after 16:30h ≥20% conferred an HR for the PFS of 1.44 (95% CI: 1.01-2.05, p = 0.043), but this prognostic effect was not found when including in the model the total number of ICI infusions received (HR 1.20, 95% CI: 0.83-1.75, p = 0.329). CONCLUSION: Time-of-day infusion of ICI may impact the survival of patients with advanced NSCLC. Underlying prognostic characteristics and the number of infusions received could represent conceivable confounding factors, linked to increased variance related to ICI infusion timing. Nonetheless, further studies may unravel chronobiological mechanisms modulating ICI efficacy.

RET-MAP: An International Multicenter Study on Clinicobiologic Features and Treatment Response in Patients With Lung Cancer Harboring a RET Fusion.

INTRODUCTION: Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete. METHODS: This retrospective multicenter study included patients with any-stage RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated. RESULTS: For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1-4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%-55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo [37.7-72.1] versus 16.3 mo [12.7-28.8], p < 0.0001). CONCLUSIONS: Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients.

Immune-related arthritis following pelvic radiation therapy in a patient with lung cancer receiving long-term immune checkpoint blocker treatment: Case report.

Radiotherapy can trigger immune-related out-of-field "abscopal" response. We report a patient with advanced NSCLC (non-small cell lung cancer) receiving long-term anti-PD1 (programmed cell death protein 1) who have developed out-of-field immune-related arthritis following pelvic irradiation.

Current challenges of unresectable stage III NSCLC: are we ready to break the glass ceiling of the PACIFIC trial?

Consolidation anti-programmed death-ligand 1 has become a new standard of care in unresectable stage III non-small cell lung cancer (NSCLC) following chemo-radiotherapy (CTRT), based on the results of two phase III trials. Advances remain however needed, in particular to reduce the risk of distant relapse and for treatment personalization. Newer strategies are currently being tested, including consolidation with dual immune checkpoint inhibitors (ICIs), concurrent chemo-radioimmunotherapy and (chemo)-immunotherapy induction before CTRT. One randomized phase II reported better outcomes with a double ICI consolidation as compared with durvalumab alone. Three nonrandomized phase II trials also suggested that concurrent ICI-CTRT was feasible. Within this review, we summarize the current evidence, highlight ongoing trials and discuss challenges that will ideally lead to a cure for more patients with unresectable stage III NSCLC.

Next-Generation Sequencing on Circulating Tumor DNA in Advanced Solid Cancer: Swiss Army Knife for the Molecular Tumor Board? A Review of the Literature Focused on FDA Approved Test.

FDA-approved next-generation sequencing assays based on cell-free DNA offers new opportunities in a molecular-tumor-board context thanks to the noninvasiveness of liquid biopsy, the diversity of analyzed parameters and the short turnaround time. It gives the opportunity to study the heterogeneity of the tumor, to elucidate complex resistance mechanisms and to adapt treatment strategies. However, lowering the limit of detection and increasing the panels' size raise new questions in terms of detection of incidental germline alterations, occult malignancies and clonal hematopoiesis of indeterminate potential mutations. In this review, after a technological discussion and description of the common problematics encountered, we establish recommendations in properly using these FDA-approved tests in a molecular-tumor-board context.

Clinical Utility and Outcomes Impact of Crystal Digital PCR of Sensitizing and Resistance EGFR Mutations in Patients With Advanced Non-Small Cell Lung Cancer.

BACKGROUND: EGFRm represent 15% of advanced NSCLC in European patients. LB for molecular profiling offers a non-invasive alternative to tissue. cdPCR is a high-sensitive and low-cost LB to detect molecular alterations. We aimed to describe cdPCR clinical utility for EGFRm detection in advanced NSCLC. METHODS: Prospective blood sample collection in patients with advanced NSCLC harbouring EGFRm either at diagnosis, under response or at PD between January 16 and September 20 at Gustave Roussy. LB was performed by cdPCR (Stilla): sensitizing (exon19; exon21 [p.L858R]) and exon 20 p.T790M resistance EGFRm. We defined high tumour burden (high-TB) as >2 metastatic sites. We analysed EGFRm detection by cdPCR and its correlation with progression-free and overall survival (PFS, OS). RESULTS: A total of 252 blood samples were collected in 140 patients. At baseline (n=25), sensitizing EGFRm were detected in 64% of samples, 88% in patients with high-TB (n=8) and 40% among those with intracranial/intrathoracic isolated lesions (n=5). At PD to tyrosine-kinase inhibitors (TKI) (n=117), detection rate (sensitizing EGFRm) was 56%; 30% in patients with intracranial/thoracic isolated lesions (n=37) vs. 67% in those with high-TB (n=63). At PD to first/second generation TKI (n=81), the p.T790M mutation was found in 22% (18/81); detection rate was 9% for intracranial/thoracic (n=23) vs. 32% for high-TB (n=41) cases. The clearance of EGFRm allelic frequency was correlated with radiological response. The absence of EGFRm detection at TKI-failure was associated with longer OS (39.1 vs. 18.4 months; P=.02). CONCLUSIONS: cdPCR is a sensitive LB for sensitizing and resistance EGFRm detection. cdPCR positivity was more likely observed in systemic PD cases with high-TB. It is a low-cost EGFRm detecting approach to guide treatment in NSCLC, however metastatic profile should be taken into account.

PARP Inhibition, a New Therapeutic Avenue in Patients with Prostate Cancer.

Up to 25% of patients with metastatic prostate cancer present with germline or somatic DNA damage repair alterations, some of which are associated with aggressive disease and poor outcomes. New data have brought poly(ADP-ribose) polymerase (PARP) inhibitors into sharp focus in the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Olaparib improved survival after at least one new hormonal therapy (NHT) in a cohort of patients harboring BRCA1, BRCA2 or ATM mutations in the PROfound trial, while rucaparib, talazoparib and niraparib demonstrated compelling activity in phase II trials. While patients with prostate cancer and BRCA1 or BRCA2 mutations may derive greatest benefit of PARP inhibition, the magnitude of benefit seems much lower in the context of most other homologous recombination gene mutations. Several PARP inhibitors are currently developed in combination with conventional therapy, including chemotherapy, NHT, and alpha-particle emitters, at different disease stages. Herein, we review the rationale for PARP inhibition in patients with prostate cancer, discuss the impact of PARP inhibitors on outcomes, and explore underlying challenges for future developments.