Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer

Clarke, Noel W.; Armstrong, Andrew J.; Thiery‐Vuillemin, Antoine; Oya, Mototsugu; Shore, Neal D.; Loredo, Eugenia; Procopio, Giuseppe; Menezes, Juliana de; Girotto, Gustavo; Arslan, Çağatay; Mehra, Niven; Parnis, Francis; Brown, Emma; Schlürmann, Friederike; Joung, Jae Young; Sugimoto, Mikio; Virizuela, Juan Antonio; Emmenegger, Urban; Navrátil, Jiří; Buchschacher, Gary L.; Poehlein, Christian; Harrington, Elizabeth A.; Desai, Chintu; Kang, Jinyu; Saad, Fred

doi:10.1056/evidoa2200043

Cited by 192 publications

(175 citation statements)

References 26 publications

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“…As several randomised controlled trials are investigating PARP inhibitors in combination with NHAs, the effect of these combinations on HRQOL is an important question. In particular, the phase 3 study PROpel (NCT03732820) was initiated to validate the efficacy and safety of olaparib plus abiraterone in the first-line setting, 30 and these results will add to the understanding of patients' HRQOL for this combination, which we have previously reported to have higher efficacy than abiraterone monotherapy. submitted work and fees from AstraZeneca, Astellas, Bayer, BMS, Eisai, Ferring, Ipsen, Janssen, Merck and Co, MSD, Pfizer, Roche, and Sanofi outside the submitted work.…”

Section: Discussionmentioning

confidence: 99%

Patient-reported outcomes with olaparib plus abiraterone versus placebo plus abiraterone for metastatic castration-resistant prostate cancer: a randomised, double-blind, phase 2 trial

Saad

Thiery‐Vuillemin²,

Wiechno³

et al. 2022

The Lancet Oncology

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Section: Discussionmentioning

confidence: 99%

Patient-reported outcomes with olaparib plus abiraterone versus placebo plus abiraterone for metastatic castration-resistant prostate cancer: a randomised, double-blind, phase 2 trial

Saad

Thiery‐Vuillemin²,

Wiechno³

et al. 2022

The Lancet Oncology

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“…A pilot study (NCI 9012) showed no differences in response rates between CRPC cohorts receiving abiraterone versus abiraterone/veliparib [ 38 ]. Abiraterone/olaparib, however, was effective in unselected patients with CRPC compared to abiraterone only [ 11 ], in particular, in a subgroup of patients with pathogenic mutations in HR DNA repair genes (NCT03732820) [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Androgen Receptor Splice Variants Contribute to the Upregulation of DNA Repair in Prostate Cancer

Tolkach

Kremer

Lotz

et al. 2022

Cancers

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Background: Canonical androgen receptor (AR) signaling regulates a network of DNA repair genes in prostate cancer (PCA). Experimental and clinical evidence indicates that androgen deprivation not only suppresses DNA repair activity but is often synthetically lethal in combination with PARP inhibition. The present study aimed to elucidate the impact of AR splice variants (AR-Vs), occurring in advanced or late-stage PCA, on DNA repair machinery. Methods: Two hundred and seventy-three tissue samples were analyzed, including primary hormone-naïve PCA, primary metastases, hormone-sensitive PCA on androgen deprivation therapy (ADT) and castration refractory PCA (CRPC group). The transcript levels of the target genes were profiled using the nCounter platform. Experimental support for the findings was gained in AR/AR-V7-expressing LNCaP cells subjected to ionizing radiation. Results: AR-Vs were present in half of hormone-sensitive PCAs on androgen deprivation therapy (ADT) and two-thirds of CRPC samples. The presence of AR-Vs is highly correlated with increased activity in the AR pathway and DNA repair gene expression. In AR-V-expressing CRPC, the DNA repair score increased by 2.5-fold as compared to AR-V-negative samples. Enhanced DNA repair and the deregulation of DNA repair genes by AR-V7 supported the clinical data in a cell line model. Conclusions: The expression of AR splice variants such as AR-V7 in PCA patients following ADT might be a reason for reduced or absent therapy effects in patients on additional PARP inhibition due to the modulation of DNA repair gene expression. Consequently, AR-Vs should be further studied as predictive biomarkers for therapy response in this setting.

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“…This is unsurprising, since PARP inhibitors are currently only approved as a later-line therapy. However, recent randomized trials in mCRPC testing upfront combinations of PARP inhibitors and androgen receptor signaling inhibitors may provide the impetus for a shift towards earlier NGS testing in prostate cancer (23,24).…”

Section: Discussionmentioning

confidence: 99%

Clinical actionability and utilization of next-generation sequencing for prostate cancer in a changing treatment landscape

Griffin¹,

Tsao²,

Patel³

et al. 2022

Front. Urol.

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BackgroundUntil recently there were no genome-directed therapies (GDTs) requiring next-generation sequencing (NGS) in prostate cancer. We examined whether the US approval of poly-(ADP-ribose) polymerase (PARP) inhibitors in May 2020 influenced the actionability and utilization of NGS in patients with prostate cancer.MethodsThis was a single-center, retrospective study including men with prostate cancer who received NGS testing from a single lab between 7/11/2018-7/6/2021. Clinical and testing data were derived from the electronic medical record.ResultsThere were 346 patients with prostate cancer and qualifying NGS testing during the study period. Overall, 55 patients (15.9%) had qualifying homologous recombination repair (HRR) alterations for PARP inhibitor treatment. A greater proportion of alterations were actionable post-approval compared to pre-approval (22.7% vs 0%, Chi-squared p<0.001). 9 patients received olaparib during the study period. Patients receiving NGS testing after the PARP inhibitor approval were more likely to have metastatic disease than patients sequenced before the approval (74.2% vs. 41.1% Chi-squared p<0.001). Only 10.4% of patients with metastatic prostate cancer received NGS testing within 30 days of diagnosis. NGS testing was performed after a median of 1 prior line of systemic therapy. The median number of days between metastatic diagnosis and NGS testing was 196 (Q1-Q3: 54-832). The median time from NGS testing to the next treatment was 255 days (95% CI 151-300). These characteristics were not significantly different before or after the PARP inhibitor approval.ConclusionIn this single-center cohort, the approval of PARP inhibitors for later-line treatment of metastatic prostate cancer increased the actionability of NGS findings but did not lead to earlier use of NGS testing.

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Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer

Cited by 192 publications

References 26 publications

Patient-reported outcomes with olaparib plus abiraterone versus placebo plus abiraterone for metastatic castration-resistant prostate cancer: a randomised, double-blind, phase 2 trial

Patient-reported outcomes with olaparib plus abiraterone versus placebo plus abiraterone for metastatic castration-resistant prostate cancer: a randomised, double-blind, phase 2 trial

Androgen Receptor Splice Variants Contribute to the Upregulation of DNA Repair in Prostate Cancer

Clinical actionability and utilization of next-generation sequencing for prostate cancer in a changing treatment landscape

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