Optimal sequencing of enzalutamide and abiraterone plus prednisone in metastatic castration-resistant prostate cancer: a multi-centre, randomized, phase II trial

Lancet Oncology (2019) • Khalaf DJ*, Annala M*, Taavitsainen S, Finch DL, Oja C, Vergidis J, Zulfiqar M, Sunderland K, Azad AA, Kollmannsberger CK, Eigl BJ, Noonan K, Wadhwa D, Attwell A, Keith B, Ellard SL, Le L, Gleave ME, Wyatt AW, Chi KN

In this multi-centre randomized phase II crossover trial, we investigated the relative efficacy of abiraterone and enzalutamide in 202 patients with metastatic castration resistant prostate cancer (mCRPC). These two androgen receptor pathway inhibitors are standard therapies in mCRPC, but had not previously been compared head-to-head. The results from our trial demonstrate that abiraterone has minimal efficacy after progression on enzalutamide, while enzalutamide can retain efficacy after progression on abiraterone.

Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer

Cancer Discovery (2018) • Annala M, Vandekerkhove G, Khalaf D, Taavitsainen S, Beja K, Warner EW, Sunderland K, Kollmannsberger C, Eigl BJ, Finch D, Oja CD, Vergidis J, Zulfiqar M, Azad AA, Nykter M, Gleave ME, Wyatt AW, Chi KN

In this study, we analyzed plasma cell-free DNA biopsies collected from 202 patients participating in a randomized phase II crossover trial comparing abiraterone and enzalutamide in metastatic castration resistant prostate cancer. We showed that circulating tumor DNA abundance in blood, along with TP53 alterations and homologous recombination repair pathway defects detected in circulating tumor DNA associate with poor treatment response. We also demonstrated that somatic genomic rearrangements producing ligand-independent AR isoforms can be detected in circulating tumor DNA.

Circulating tumour DNA abundance and potential utility in de novo metastatic prostate cancer

European Urology (2019) • Vandekerkhove G*, Struss WJ*, Annala M*, Kallio HM, Khalaf D, Warner EW, Herberts C, Ritch E, Beja K, Loktionova Y, Hurtado-Coll A, Fazli L, So A, Black PC, Nykter M, Tammela T, Chi KN, Gleave ME

In this study, we analyzed plasma cell-free DNA samples collected from 53 patients with newly diagnosed metastatic castration-sensitive prostate cancer, and found a detectable circulating tumor DNA fraction in 74% of patients. We also showed that circulating tumor DNA is eliminated from the bloodstream within a week after initiation of androgen deprivation therapy. Finally, we demonstrated high concordance for somatic mutations detected in diagnostic tissue biopsies and plasma cell-free DNA biopsies.

Concordance of circulating tumor DNA and matched metastatic tissue biopsy in prostate cancer

Journal of the National Cancer Institute (2017) • Wyatt A*, Annala M*, Aggarwal R, Beja K, Feng F, Youngren J, Foye A, Lloyd P, Nykter M, Beer TM, Alumkal JJ, Thomas GV, Reiter RE, Rettig MB, Evans CP, Gao AC, Chi KN, Small EJ, Gleave ME

In this study, we analyzed 45 pairs of time-matched metastatic tissue biopsies and plasma cell-free DNA biopsies collected from 42 patients with metastatic prostate cancer. We showed that 76% of cell-free DNA samples had a detectable level of ctDNA, and that 94% of somatic mutations detected in metastatic tissue were concordantly detected in matched cell-free DNA samples. This was the first published study systematically comparing a large cohort of metastatic tissue biopsies and cell-free DNA biopsies in the context of metastatic prostate cancer.

Identification of hypermutation and defective mismatch repair in ctDNA from metastatic prostate cancer

Clinical Cancer Research (2019) • Ritch E*, Fu SYF*, Herberts C*, Wang G, Warner EW, Schönlau E, Taavitsainen S, Murtha AJ, Vandekerkhove G, Beja K, Loktionova Y, Khalaf D, Fazli L, Kushnir I, Ferrario C, Hotte S, Annala M, Chi KN, Wyatt AW

In this study, we analyzed plasma cell-free DNA samples from 433 metastatic prostate cancer patients with detectable circulating tumor DNA, and identified 16 patients with a hypermutator phenotype driven by a defective DNA mismatch repair pathway. These patients exhibited a tendency towards tumor suppressor inactivation by mutation rather than copy number loss, and a high frequency of hotspot mutations in AKT1, PIK3CA, CTNNB1, and the AR ligand binding domain. They also had a poor clinical prognosis and exhibited high clonal diversity.

Treatment outcomes and tumor loss-of-heterozygosity in germline DNA repair deficient prostate cancer

European Journal of Urology (2017) • Annala M, Struss WJ, Warner EW, Beja K, Vandekerkhove G, Wong A, Khalaf D, Seppälä I-L, So A, Lo G, Aggarwal R, Small EJ, Nykter M, Gleave ME, Chi KN, Wyatt AW

In this study, we analyzed targeted germline sequencing data from 319 patients with metastatic castration resistant prostate cancer, and confirmed previous reports that 8 - 12% of these patients harbor germline defects disrupting the homologous recombination repair (HRR) pathway. We showed preliminary evidence that these patients have a poor prognosis on initial androgen deprivation therapy. We also collected plasma cell-free DNA biopsies from multiple patients, and demonstrated that germline defects in the HRR pathway were accompanied with somatic loss-of-heterozygosity in almost all cases, and that these loss-of-heterozygosity events could be detected in circulating tumor DNA.

Circulating tumor DNA reveals clinically-actionable somatic genome of metastatic bladder cancer

Clinical Cancer Research (2017) • Vandekerkhove GR*, Todenhöfer T*, Annala M*, Struss WJ, Wong A, Beja K, Ritch E, Brahmbhatt S, Volik S, Hennenlotter J, Nykter M, Chi KN, North S, Stenzl A, Collins CC, Eigl BJ, Black PC, Wyatt AW

In this study, we analyzed plasma cell-free DNA biopsies collected from 51 patients with aggressive bladder cancer, including 37 patients with metastatic disease. We showed that the majority of patients with metastatic bladder cancer carry detectable levels of circulating tumor DNA in their blood, enabling genomic characterization. This was the first published study testing the efficacy of plasma cell-free DNA biopsies in aggressive bladder cancer.

Frequent mutation of the FOXA1 untranslated region in prostate cancer

Nature Communications Biology (2018) • Annala M*, Taavitsainen S*, Vandekerkhove G, Bacon J, Beja K, Chi KN, Nykter M, Wyatt AW

In this study, we sequenced the untranslated regions of 72 established driver genes in 712 plasma cell-free DNA samples collected from patients with metastatic prostate cancer and identified FOXA1 3'-UTR mutations in 12% of patients. The indel-dominant pattern of somatic mutation extended into the FOXA1 coding region, where it was shaped by clonal selection to yield a cluster of non-frameshift indels inside the forkhead domain.

Moving toward personalized care: liquid biopsy predicts response to cisplatin in an unusual case of BRCA2-null neuroendocrine prostate cancer

Clinical Genitourinary Cancer (2016) • Chedgy E, Annala M, Beja K, Warner EW, Gleave ME, Chi KN, Wyatt AW

In this case study, we used a plasma cell-free DNA biopsy and metastatic tissue biopsy to identify a somatic biallelic BRCA2 loss in a patient with metastatic neuroendocrine prostate cancer. The patient exhibited a dramatic response to platinum therapy and subsequent treatment with PARP inhibitors, and now several years later remains in complete remission. Resistance against PARP inhibitor treatment in BRCA2-defective patients typically arises through reversion mutations that recover the function of at least one BRCA2 copy. In a patient with BRCA2 biallelic deletion, this type of resistance cannot arise.