Pembrolizumab plus Olaparib in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort A Study

Yu, Evan Y.; Piulats, Josep María; Gravis, G.; Fong, Peter; Todenhöfer, Tilman; Laguerre, Brigitte; Arranz, José Ángel; Oudard, Stéphane; Massard, Christophe; Heinzelbecker, Julia; Nordquist, Luke T.; Carles, Joan; Kolinsky, Michael; Augustin, Marinela; Tafreshi, Ali; Li, Xin Tong; Qiu, Ping; Poehlein, Christian; Schloss, Charles; Bono, Johann S. de

doi:10.1016/j.eururo.2022.08.005

Cited by 34 publications

(24 citation statements)

References 34 publications

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“…HRR alterations were not required for enrollment, and it should be noted that there were challenges with assessment of HRR status in this study due to issues with the ctDNA assay used in the early part of this trial. In cohort A, patients are administered pembrolizumab 200mg IV every 3 weeks plus olaparib 400mg PO twice daily ( 23 ). The primary endpoints in this study are safety, PSA 50 , and ORR per blinded independent central review.…”

Section: Parpi Combination Strategiesmentioning

confidence: 99%

PARP inhibitors in metastatic prostate cancer

et al. 2023

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Poly-ADP ribose polymerase inhibitors (PARPi) are an emerging therapeutic option for the treatment of prostate cancer. Their primary mechanism of action is via induction of synthetic lethality in cells with underlying deficiencies in homologous recombination repair (HRR). In men with metastatic castrate-resistant prostate cancer (mCRPC) and select HRR pathway alterations, PARPi treatment has been shown to induce objective tumor responses as well as improve progression free and overall survival. Presently, there are two PARPi, olaparib and rucaparib, that are FDA approved in the treatment of mCRPC. Ongoing research is focused on identifying which HRR alterations are best suited to predict response to PARPi so that these therapies can be most effectively utilized in the clinic. While resistance to PARPi remains a concern, combination therapies may represent a mechanism to overcome or delay resistance.

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Section: Parpi Combination Strategiesmentioning

confidence: 99%

PARP inhibitors in metastatic prostate cancer

et al. 2023

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“…A phase II trial [ 94 ] enrolled 17 patients with mCRPC for treatment with Durvalumab, an immune checkpoint inhibitor and olaparib. PSA or radiologic progression occurred in 53% of patients [ 95 ]. CHeckMate 9KD [ 100 ] is a phase II trial assessing the safety and efficacy of nivolumab, a PD-1 inhibitor, in combination with rucaparib, docetaxel or enzalutamide in patients with mCRPC.…”

Section: Resultsmentioning

confidence: 99%

Advances in PARP Inhibitors for Prostate Cancer

Tisseverasinghe

Bahoric

Anidjar

et al. 2023

Cancers

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Poly-adenosine diphosphate-ribose polymerase plays an essential role in cell function by regulating apoptosis, genomic stability and DNA repair. PARPi is a promising drug class that has gained significant traction in the last decade with good outcomes in different cancers. Several trials have sought to test its effectiveness in metastatic castration resistant prostate cancer (mCRPC). We conducted a comprehensive literature review to evaluate the current role of PARPi in this setting. To this effect, we conducted queries in the PubMed, Embase and Cochrane databases. We reviewed and compared all major contemporary publications on the topic. In particular, recent phase II and III studies have also demonstrated the benefits of olaparib, rucaparib, niraparib, talazoparib in CRPC. Drug effectiveness has been assessed through radiological progression or overall response. Given the notion of synthetic lethality and potential synergy with other oncological therapies, several trials are looking to integrate PARPi in combined therapies. There remains ongoing controversy on the need for genetic screening prior to treatment initiation as well as the optimal patient population, which would benefit most from PARPi. PARPi is an important asset in the oncological arsenal for mCRPC. New combinations with PARPi may improve outcomes in earlier phases of prostate cancer.

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“…Even though there are studies that have investigated PARP inhibitor treatment such as olaparib and rucaparib, few have investigated their synergistic effects with ICIs [ 29 ]. However, cohort A of the KEYNOTE 365 study investigated pembrolizumab plus olaparib in 102 docetaxel-pretreated mCRPC patients with disease progression [ 30 ]. A total of 59 patients had measurable disease, with an ORR of 8.5%.…”

Section: Novel Immunotherapeutic Targets Beyond Icimentioning

confidence: 99%

Metastatic Castration-Resistant Prostate Cancer, Immune Checkpoint Inhibitors, and Beyond

et al. 2023

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The therapeutic landscape of several genitourinary malignancies has been revolutionized by the development of immune checkpoint inhibitors (ICIs); however, the utility of immunotherapies in prostate cancer has been limited, partly due to the immunologically “cold” tumor terrain of prostate cancer. As of today, pembrolizumab is the only immune checkpoint inhibitor approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) in a select group of patients with high microsatellite instability (MSI-H), deficient mismatch repair (dMMR), or high tumor mutational burden (TMB). Looking ahead, several combinatorial approaches with ICIs involving radioligands, radiotherapy, PARP inhibitors, interleukin inhibitors, and cancer vaccines are exploring a potential synergistic effect. Furthermore, B7-H3 is an alternative checkpoint that may hold promise in adding to the treatment landscape of mCRPC. This review aims to summarize previous monotherapy and combination therapy trials of ICIs as well as novel immunotherapy combination therapeutic strategies and treatment targets in mCRPC.

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Pembrolizumab plus Olaparib in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort A Study

Cited by 34 publications

References 34 publications

PARP inhibitors in metastatic prostate cancer

PARP inhibitors in metastatic prostate cancer

Advances in PARP Inhibitors for Prostate Cancer

Metastatic Castration-Resistant Prostate Cancer, Immune Checkpoint Inhibitors, and Beyond

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