Now the dust has settled over immune checkpoint blockade in metastatic prostate cancer
Authors: N. Mehra, W. Gerritsen
Journal: Annals of Oncology (2018)

Since the first-in-man trial of the programmed cell death-1 (PD-1) inhibitor nivolumab in patients with solid tumors, attention mainly focused to the cohorts where spectacular responses were witnessed, including non-small-cell lung, melanoma and renal cell cancer patients [1.Topalian S.L. Hodi F.S. Brahmer J.R. et al.Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med. 2012; 366: 2443-2454Crossref PubMed Scopus (9269) Google Scholar]. Among the nivolumab cohort of 17 patients with advanced castration-resistant prostate cancer (CRPC), no activity was witnessed, and prostate cancer was effectively classified as a nonresponsive ‘cold’ tumor for single-agent anti-PD-1 immune checkpoint blockade (ICB). However, following the first approvals of ICB in solid cancers, a reinvigorated interest in prostate cancer slowly established, due to preclinical data suggesting immunomodulatory priming with an androgen-receptor signaling agent could induce ICB responsiveness [2.Bishop J.L. Sio A. Angeles A. et al.PD-L1 is highly expressed in Enzalutamide resistant prostate cancer.Oncotarget. 2015; 6: 234-242Crossref PubMed Scopus (199) Google Scholar]. In this issue of Annals of Oncology, Hansen et al. present the final safety and efficacy data of the Keynote-028 study, in which 23 patients with CRPC were treated with pembrolizumab if PD-L1 expression was present on ≥1% of tumor and/or stroma cells [3.Hansen A.R. Massard C. Ott P.A. et al.Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study.Ann Oncol. 2018; 29: 1807-1813Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar]. An objective response per RECIST v1.1 (primary end point) of 17.4% is seen with four partial responses; quite remarkable was the median duration of 13.5 months in responding patients and a disease control rate (DCR) of at least 6 months in 30.4% of patients. From a safety perspective, onset of a grade 3 peripheral neuropathy was witnessed in one patient previous treated with taxane chemotherapy, without any new insights. The response rates seen in the Keynote-028 trial compare with recent data of monotherapy anti-PD-1 ICB in advanced prostate cancer were in a limited number of unselected patients, a biochemical response rate was seen between 17% and 19% for pembrolizumab and nivolumab [4.Higa J. Wilenius K. Weidhaas J.B. et al.Pembrolizumab for recurrent or advanced prostate cancer.J Clin Oncol. 2018; 36Google Scholar, 5.Smits M. Doelen M.J. Van Der Westdorp H. et al.Immunological and genomic correlates of response to anti-PD1 checkpoint therapy in mismatch proficient and deficient patients with metastatic castration resistant prostate cancer.J Clin Oncol. 2018; 36: 3-4Google Scholar]. Interim data from the phase II Keynote-199 trial of single-agent pembrolizumab was recently presented for 198 patients with measurable disease, with and without PD-L1 expression (n = 131 and n = 67, respectively), and in 60 patients with bone-only disease [6.de Bono J.S. Goh J.C. Ojamaa K. et al.Keynote-199: pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC).J Clin Oncol. 2018; 36Google Scholar]. In the 198 patients with measurable disease, only 5% of patients witnessed an objective response, with 2 CR and 7 PR; 11% of patients in all three cohorts witnessed a clinical meaningful DCR of at least 6 months. There is a manifest difference in ORR between the Keynote-028 and the 199 trial, which can not easily be explained. Patient inclusion criteria do differ, with patients recruited to the 028 trial having a more advanced disease, and a median of 4 lines of prior therapies. Since 2016, several trials have reported (interim) results on additional immune-checkpoint agents or combinatory regimens in CRPC patients. These include phase I data of the anti-PD-L1 agent avelumab [7.Fakhrejahani F. Madan R.A. Dahut W.L. et al.Avelumab in metastatic castration-resistant prostate cancer (mCRPC) (NCT01772004).J Clin Oncol. 2017; 35Google Scholar], enzalutamide beyond progression in combination with pembrolizumab [8.Graff J.N. Alumkal J.J. Drake C.G. et al.Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer.Oncotarget. 2016; 7: 52810-52817Crossref PubMed Scopus (265) Google Scholar], nivolumab in combination with ipilimumab for patients expressing the androgen-receptor splice variant 7 (AR-v7) [9.Boudadi K. Suzman D.L. Luber B. et al.Phase 2 biomarker-driven study of ipilimumab plus nivolumab (Ipi/Nivo) for ARV7-positive metastatic castrate-resistant prostate cancer mCRPC.J Clin Oncol. 2017; Crossref Google Scholar], and durvalumab in combination with olaparib in patients unselected for DNA damage repair defects [10.Karzai F. Madan R.A. Owens H. et al.Combination of PDL-1 and PARP inhibition in an unselected population with metastatic castrate-resistant prostate cancer (mCRPC) (NCT02484404).J Clin Oncol. 2017; 35: 162Crossref Google Scholar]. At time of this editorial, at least 25 ICB trials are recruiting patients with CRPC, or are awaiting results. A selection from key phase I–III trials is presented in Table 1.Table 1Selected phase I-III trials in castration-resistant prostate cancer utilizing immune-checkpoint inhibitorsPhaseAnti-PD-1 ICBAgent 2nIndication/populationExpected resultsAcronym/nameNCT3Pembrolizumab370Post-docetaxel, cohort 1-32018/2020MK-3475-199/ Keynote-199027870052Avelumab18Neuroendocrine prostate cancer2022PICK-NEPC031794101Avelumab1758Multiple cohorts, including CRPC2018Javelin Solid Tumor017720042NivolumabIpilimumab90Predocetaxel2022CheckMate 650029859572DurvalumabTremelimumab27Predocetaxel2020032048122DurvalumabTremelimumab74Predocetaxel, randomized open-label D ± T2018027887731AtezolizumabSipuleucel-T34Arm 1 and 2 by sequence of both drugs2019030242162PembrolizumabHER2Bi-armed T-cells332019034068581/2NivolumabPROSTVAC (rilimogene)10/?Safety part in pts with CPRC, neadjuvant regimen in HSPC2020029332552PembrolizumabRadium-22345Pre- and post-docetaxel2024030934281AtezolizumabRadium-22345Predocetaxel2020028146693PembrolizumabEnzalutamidePredocetaxel, cohort 4 and 52020MK-3475-199/ Keynote-199027870053AtezolizumabEnzalutamide730Predocetaxel, randomized open-label2022IMbassador250030163121b/2PembrolizumabOlaparib, Docetaxel, Enzalutamide180Pre- and postdocetaxel2020MK-3475-365/ Keynote-365028615732NivolumabDocetaxel, Enzalutamide, Rucaparib3002020CheckMate 9KD033387902AtezolizumabCabozantinib360Multiple cohorts, including expansion cohort 6 with CRPC2020COSMIC XLS184-021031709602AvelumabTalozaparib316Experimental E1 cohort and E2 (with DDR defect)2020033304052JNJ-63723283Niraparib60BM+ and BM– cohorts for DDR2020034313502PembrolizumabARRx (ASO)382023ARRO-CITO033005052PembrolizumabNavarixin120Multiple cohorts including CRPC2019034739252PembrolizumabADXS31-14251Received < 3 prior systemic regimens2019Keynote-046023255571DurvalumabAZD4635156Multiple cohorts with phase Ib in mCRPCSelected ongoing trials for patients with castration-resistant prostate cancer currently recruiting or awaiting results. Open table in a new tab Selected ongoing trials for patients with castration-resistant prostate cancer currently recruiting or awaiting results. If single-agent ICB benefits only a minority of patients with mCRPC (11%–30% show at least 6 months clinical benefit), one of the major challenges will be defining which histopathological and molecular characteristics should be used to select for those susceptible for ICB. The tumor mutational burden, the number of small insertions and deletions (indels), focal tandem duplications and number of gene fusions are all strongly related with the number of neoepitopes and a stochastic probability to result in immune recognition of ‘nonself’ tumor antigens [11.McGranahan N. Furness A.J.S. Rosenthal R. et al.Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.Science. 2016; 351: 1463-1469Crossref PubMed Scopus (1944) Google Scholar, 12.Wu Y.M. Cieślik M. Lonigro R.J. et al.Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer.Cell. 2018; 173: 1770-1782Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 13.Turajlic S. Litchfield K. Xu H. et al.Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis.Lancet Oncol. 2017; 2045doi:10.1016/S1470-2045(17)30516-8Google Scholar]. Molecular stratification of prostate cancer subgroups with a higher rate of neoantigen formation, include those with mismatch-repair deficiency (MMRd) and POLE mutation. MMRd cancer is more prone to respond to monotherapy anti-PD-1/PD-L1 ICB [14.Le D.T. Durham J.N. Smith K.N. et al.Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.Science. 2017; 357: 409-413Crossref PubMed Scopus (3762) Google Scholar, 15.Administration USF& D. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm (23 June 2018, date last accessed).Google Scholar]. A handful reports corroborated responsiveness of ICB in MMRd prostate cancer [5.Smits M. Doelen M.J. Van Der Westdorp H. et al.Immunological and genomic correlates of response to anti-PD1 checkpoint therapy in mismatch proficient and deficient patients with metastatic castration resistant prostate cancer.J Clin Oncol. 2018; 36: 3-4Google Scholar, 8.Graff J.N. Alumkal J.J. Drake C.G. et al.Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer.Oncotarget. 2016; 7: 52810-52817Crossref PubMed Scopus (265) Google Scholar, 14.Le D.T. Durham J.N. Smith K.N. et al.Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.Science. 2017; 357: 409-413Crossref PubMed Scopus (3762) Google Scholar, 16.Schweizer M.T. Cheng H.H. Tretiakova M.S. et al.Mismatch repair deficiency may be common in ductal adenocarcinoma of the prostate.Oncotarget. 2016; 7: 82504-82510Crossref PubMed Scopus (55) Google Scholar, 17.Basnet A. Khullar G. Mehta R. Chittoria N. A case of locally advanced castration-resistant prostate cancer with remarkable response to nivolumab.Clin Genitourin Cancer. 2017; 15: e881-e884Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar] with biochemical responses witnessed in over half of patients. DNA-damage repair defects (including homologous recombination defects in genes including BRCA1, BRCA2, ATM, CHEK2) and those with instable chromosomal prostate cancer (particular biallelic CDK12 aberrations) [12.Wu Y.M. Cieślik M. Lonigro R.J. et al.Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer.Cell. 2018; 173: 1770-1782Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 19.Haffner M.C. Guner G. Taheri D. et al.Comprehensive evaluation of PD-L1 expression in primary and metastatic prostate cancer.Am J Pathol. 2018; 188: 1478-1485Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 18.Robinson D. Van Allen E.M. Wu Y.-M. et al.Integrative clinical genomics of advanced prostate cancer.Cell. 2015; 161: 1215-1228Abstract Full Text Full Text PDF PubMed Scopus (1990) Google Scholar], define mutational subtypes of mCRPC that could be enriched for in future trials with IBC. Increased PD-L1 expression on tumor and/or immune cells is associated with augmented response to anti-PD-1/PD-L1 ICB, particularly in lung, melanoma and less clearly in bladder cancer. Conflicting studies on proportion of PD-L1 positive prostate tumors are reported. A recent report by Hafner et al. studied 57 mCRPC specimens and found evidence PDL-1 expression on tumor cells (clone SP263) of 32% [20.Wellenstein M.D. de Visser K.E. Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape.Immunity. 2018; 48: 399-416Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar], while Hansen found PD-L1 expression in 14% of tumor specimens (clone 22C3), of which approximately half of cases had PD-L1 expression ≥1% on prostate cancer cells and half on immune cells. The interim data from the Keynote-199 trial taught us that the ORR to IBC is independent of PD-L1 expression (clone 22C3). PD-L1 expression on prostate cancer cells shows no clear relation with mutational load, as immune-infiltration and adaptive PD-L1 expression is partly driven by indels or gene fusion-induced neo-antigen formation, and infrequently due to genomic amplification or aberration of the PD-L1 gene locus. Hansen et al. give further evidence that ICB could be added to the armamentarium of anti-cancer drugs for patients with prostate cancer, however the current evidence strongly indicates that ICB is not for all-comers, and PD-L1 expression is not predictive for response to ICB in prostate cancer. The Keynote 028 did not incorporate translational studies, including next-generation sequencing or immunohistochemical analyses to dissect the remarkable and durable responses witnessed. The significant differences in ORR between the small studies are likely due to differences in patient inclusion for immunogenic genotypes, as we have seen in the combination study of enzalutamide with pembrolizumab, where MMRd was confirmed in at least one of the patients with deep and durable response [8.Graff J.N. Alumkal J.J. Drake C.G. et al.Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer.Oncotarget. 2016; 7: 52810-52817Crossref PubMed Scopus (265) Google Scholar]. Identification and prospective validation of predictive biomarkers for response to IBC will prove vital for the success of ICB for molecularly selected patients with castration-resistant prostate cancer. A larger proportion of patients may derive benefit from trials utilizing a backbone of anti-PD-1 or PD-L1 immunotherapy in combinatory regimens with registered or experimental agents targeting prostate cancer. Recent interim data on the combination durvalumab and olaparib attracted attention due the proportion of patients with durable responses that had proven DNA damage repair defects (progression-free survival of 16.1 months), with a biochemical response rate of 47% in the full set of patients and 52% of patients showing no radiographic progression at 12 months. The added value of durvalumab will have to be demonstrated in a future randomized trial. As patient selection is of paramount significance, research should focus on integrating biomarkers into a prostate cancer ‘immunogram’, that should include tumour mutational burden, putative immunogenic signatures or genetic aberrations, immunosuppressive genetic background (chromosome 8q or Myc amplification and PTEN loss-of-function) [20.Wellenstein M.D. de Visser K.E. Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape.Immunity. 2018; 48: 399-416Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 21.Peng W. Chen J.Q. Liu C. et al.Loss of PTEN promotes resistance to T cell-mediated immunotherapy.Cancer Discov. 2016; 6: 202-216Crossref PubMed Scopus (928) Google Scholar], tumour-infiltrating lymphocytes, myeloid-derived suppressor cells, and additional factors like IDO-1 expression. Ideally, non-invasive assessment of tumour mutational burden and assessment of mutational immunogenic subtypes need detection in liquid biopsies, feasible due to high levels of circulating tumour DNA and circulating tumour cells, to maximize patient selection for ICB in prostate cancer. None declared.