Olaparib for Metastatic Castration-Resistant Prostate Cancer

Bono, Johann S. de; Mateo, Joaquín; Fizazi, Karim; Saad, Fred; Shore, Neal D.; Sandhu, Shahneen; N., Kim; Sartor, Oliver; Agarwal, Neeraj; Olmos, David; Thiery‐Vuillemin, Antoine; Twardowski, Przemyslaw; Mehra, Niven; Goessl, Carsten; Kang, Jinyu; Burgents, Joseph E.; Wu, Weiwen; Kohlmann, Alexander; Adelman, Carrie A.; Hussain, Maha

doi:10.1056/nejmoa1911440

Cited by 1,651 publications

(1,588 citation statements)

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“…Our current study also identified a highly significant enrichment for alterations affection DNA homologous recombination repair genes including BRCA2, BRCA1 and ATM. Both of these observations have relevant clinical implications with regards to potential therapeutic opportunities related to MEK/ERK inhibitors for NF1 mutated patients with possible activation of the RAS/RAF/ERK signaling pathway, and PARP inhibition for patients harboring BRCA1/2 alterations, as well as other DNA repair mutations, as recently suggested by the results from the PROFOUND and TOPARP-B trials 22,34,35 . We believe these discoveries should pave the way for future exploratory biomarker-driven clinical studies with impact on patients' treatment.…”

Section: (Supplementary Figure S23)mentioning

confidence: 81%

“…Prior studies of CRPC have demonstrated alterations in genes involved in DNA homologous repair in up to 20% of cases 11,12,20 , making advanced PCa an important candidate for PARPi therapies 21,22 . In the PCBM cohort, 19 patients (67.8%) demonstrated alterations in BRCA2 with heterozygous loss or homozygous deletion and in three cases with concomitant mutations.…”

Section: (Supplementary Figure S23)mentioning

confidence: 99%

“…Patient P23 showed a frameshift mutation and patient P36 a missense mutation within their metastatic samples. To address the status of DNA HR in the PCBM cohort, we surveyed all genes known to be involved in the HR pathway, selecting alterations used as inclusion criteria in the recently reported PROfound clinical trial 22 (Figure 3). Biallelic loss (either homozygous deletion or loss of one allele together with mutation of the remaining one or 2 somatic mutations) affecting at least one of the investigated genes was found in 18% of patients (5/28).…”

Section: (Supplementary Figure S23)mentioning

confidence: 99%

“…When considering the combination of somatic mutations, copy number alteration, and Large-scale State Transitions (LST), 64.3% of PCBM patients (18/28) were affected. The significant enrichment for molecular alterations affecting the HR pathway implicates PCBM patients as potential candidates for PARPi therapy in a population of men who have not been included PROfound clinical trial 22 .…”

Section: (Supplementary Figure S23)mentioning

confidence: 99%

“…As suggested by the results from the PROfound and TOPARP-B trials 22,34,35 However, patients with known brain metastases were excluded from the PROfound trial.…”

Section: (Supplementary Figure S23)mentioning

confidence: 99%

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The Genomic Landscape of Prostate Cancer Brain Metastases

Rodrı́guez

Gallon

Akhoundova

et al. 2020

Preprint

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Lethal prostate cancer commonly metastasizes to bone, lymph nodes, and visceral organs but with more effective therapies, there is an increased frequency of metastases to the brain.Little is known about the genomic drivers of prostate cancer brain metastases (PCBM). To address this, we conducted a comprehensive multi-regional, genomic, and targeted transcriptomic analysis of PCBM from 28 patients. We compared whole-exome and targeted RNA sequencing with matched primary tumors when available (n = 10) and with publicly available genomic data from non-brain prostate cancer metastases (n = 416). In addition to common alterations in TP53, AR, RB1, and PTEN, we identified highly significant enrichment of mutations in NF1 (25% cases (6/28), q = 0.049, 95% CI = 2.38 -26.52, OR = 8.37) and RICTOR (17.9% cases (5/28), q = 0.01, 95% CI = 6.74 -480.15, OR = 43.7) in PCBM compared to non-brain prostate cancer metastases, suggesting possible activation of the druggable pathways RAS/RAF/MEK/ERK and PI3K/AKT/mTOR, respectively. Compared to non-brain prostate cancer metastases, PCBM were almost three times as likely to harbor DNA homologous repair (HR) alterations (42.9% cases (12/28), p =0.016, 95% CI = 1.17 -6.64, OR = 2.8). When considering the combination of somatic mutations, copy number alteration, and Large-scale State Transitions, 64.3% of patients (18/28) were affected. HR alterations may be critical drivers of brain metastasis that potentially provide cancer cells a survival advantage during re-establishment in a special microenvironment. We demonstrate that PCBM have genomic dependencies that may be exploitable through clinical interventions including PARP inhibition.

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Section: (Supplementary Figure S23)mentioning

confidence: 81%

Section: (Supplementary Figure S23)mentioning

confidence: 99%

Section: (Supplementary Figure S23)mentioning

confidence: 99%

Section: (Supplementary Figure S23)mentioning

confidence: 99%

“…As suggested by the results from the PROfound and TOPARP-B trials 22,34,35 However, patients with known brain metastases were excluded from the PROfound trial.…”

Section: (Supplementary Figure S23)mentioning

confidence: 99%

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The Genomic Landscape of Prostate Cancer Brain Metastases

Rodrı́guez

Gallon

Akhoundova

et al. 2020

Preprint

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Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality

Martin,

Turner,

Young

et al. 2024

JAMA

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ImportanceThe Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear.ObjectiveTo evaluate the effect of a single invitation for PSA screening on prostate cancer–specific mortality at a median 15-year follow-up compared with no invitation for screening.Design, Setting, and ParticipantsThis secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021.InterventionMen received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation).Main Outcomes and MeasuresThe primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer–specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis.ResultsOf 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P &lt; .001) and localized (T1/T2: 3.6% vs 3.1%; P &lt; .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment.Conclusions and RelevanceIn this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small.Trial Registrationisrctn.org Identifier: ISRCTN92187251

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Activity of Platinum-Based Chemotherapy in Patients With Advanced Prostate Cancer With and Without DNA Repair Gene Aberrations

et al. 2020

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Key Points Question Is there a role for platinum-based treatment in molecularly selected patients with advanced prostate cancer? Findings In a case series of 508 patients, platinum-based therapy was associated with antitumor activity, especially among patients with known DNA repair gene aberrations. In patients with DNA repair gene aberrations, nearly half had a decrease in prostate-specific antigen levels of at least 50% and experienced soft tissue responses. Meaning In patients with prostate cancer and DNA repair gene aberrations, platinum-based therapy may be considered a treatment option.

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Olaparib for Metastatic Castration-Resistant Prostate Cancer

Cited by 1,651 publications

References 27 publications

The Genomic Landscape of Prostate Cancer Brain Metastases

The Genomic Landscape of Prostate Cancer Brain Metastases

Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality

Activity of Platinum-Based Chemotherapy in Patients With Advanced Prostate Cancer With and Without DNA Repair Gene Aberrations

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