ASCO 2017: Selection, Timing, and Interpretation of Metastatic Castration-Resistant Prostate Cancer Lesions

Chicago, IL (UroToday.com) During this session, Dr. Himisha Beltran presented on metastatic castration-resistant prostate cancer lesions (mCRPC), specifically regarding their management in the new age of biomarkers and “-omics”. The key question is how to translate all the “-omics” evaluations and molecular biomarkers into clinical practice.

When should we thinking about doing a biopsy of a metastatic lesion in a patient with CRPC? In her opinion, it should be considered when looking for an actionable target or to identify treatment resistance.

At this point, she began a review of the recent literature looking at the search for actionable targets. The International “Stand Up To Cancer” (SU2C) PCF Prostate Cancer Dream Team has been analyzing 150 metastatic CRPC biopsies using whole exome sequencing (WES), and they have identified DNA repair alteration in 22% of patients. Recent evidence has found similar findings in multiple solid malignancies. The usual genes are BRCA, ATM, CHEK2, PALB2, and mismatch repair genes such as MLH2, MSH2, and MSH6. Surprisingly, 8% of patients have germline mutations (and 11.8% in a larger cohort). 

Based on these genetic defects, she noted that the use of PARP inhibitors in metastatic prostate cancer1 has had success in patients with these above genetic defects. As such, PARP inhibitors have had renewed interest in patients identified to have such defects. However, as their use increases, we will likely need to start identifying and recognizing new resistance mechanisms that will inevitably develop – including BRCA reversion, loss of PARP1 expression, or up-regulation of the PgP transporter. Indeed, these genetic defects have also brought about a renewed interest in platinum-based chemotherapy – patients found to have exception response to platinum were found to have bi-allelic inactivation BRCA2

Dr. Beltran briefly introduced her research on FANCA (Fanconi A), which is important in repairing inter-strand cross-links but also regulates other DNA repair processes. As such, a 66 year old man with mCRPC with low PSA was found to have a FANCA loss. Treated with cisplatin, docetaxel and ADT, he had a 2-year durable complete response. 

A hypermutated phenotype occurs in about 5% of all mCRPC patients, and patients with hypermutated phenotype, mismatch repair defects (MMR) and microsatellite instability (MSI) have all gained prominence in the development and management of cancer. While MMR defects are known to lead to cancer (Lynch syndrome), often more aggressive cancer, many of these defects also lead to more neoantigens which may lead to better response to immune checkpoint blockade. Pembrolizumab had now received by the FDA for all cancer types with MSI or MMR loss based on multiple phase 1/2 trials – while prostate cancer was a small component of those studies, there may be a significant role in CRPC management. Maybe we need to be screening all CRPC patients for MSI or MMR defects? Current testing depends on PCR assessment for MSI, IHR for protein expression (MMR genes) or germline testing. However, we have many areas of optimization and questions to answers prior – does it require a new biopsy or primary tumor tissue sufficient? Can we use mutation rate instead? Can we use ctDNA?

How we assess matters! There are numerous techniques, and each has its benefits and limitations. The next talk by Dr. Pritchard reviews these techniques. 

When in the treatment course should we assess for actionable alterations? At diagnosis? At time of metastatic disease? At first line CRPC? Likely, we may need to assess at multiple time points along the treatment course. While actionable alterations and resistance mechanisms are enriched at later stage disease states, but even early stage disease may have some targets.

We also need to optimize the biopsy of metastatic sites. Unfortunately, or fortunately, most CRPC patients primarily have sclerotic bony metastases. While success at getting tissue at biopsy is >80% at most specialized centers, frequently there are only rare tumor cells enough for diagnosis, but not enough for additional testing and research. 

This is where there is a potential for liquid biopsies – such as circulating tumor cells (CTCs) and cfDNA (cell-free DNA). 

Obtaining this information may help then identify treatment resistance. At this point in time, most resistance in CRPC is due to re-activation of the androgen axis. However, with more and more therapies targeting the AR axis, other resistance pathways may become more prominent. These androgen-independent pathways, including androgen-receptor variants or progression to neuroendocrine phenotype, have been demonstrating to be resistant to traditional AR targeting therapies and may need to be managed differently. 

She did spend some time on neuroendocrine prostate cancer, and alluded to Abstract 5029 (Puca et al). In this abstract, ROVA-T, an anti-DLL3 drug-conjugate, which has been demonstrated to have benefit in neuroendocrine small cell lung cancer, is being assessed in neuroendocrine prostate cancer. See Urotoday conference highlights for full summary!

Ultimately, while precision medicine is the goal of cancer therapy, the main challenges in implementing precision medicine in advanced prostate cancer are:

1) Pathway cross-talk – and its implications for co-targeting
2) Phenotypic and genomic evolution
3) Molecular heterogeneity
4) Integration of the all the “-omics” evaluations, but also accounting for tumor microenvironment, immune response, etc.
5) Functional significance of novel mutations need to stringently assessed

The take-home message: Understanding the advantages and limitations of available and emerging technologies is important in guiding interpretation of results.

Presented By: Himisha Beltran, MD, Weill Cornell Medical College, New York City, NY

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto 
Twitter: @tchandra_uromd

REFERENCES:
1. Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, Nava Rodrigues D, Robinson D, Omlin A, Tunariu N, Boysen G, Porta N, Flohr P, Gillman A, Figueiredo I, Paulding C, Seed G, Jain S, Ralph C, Protheroe A, Hussain S, Jones R, Elliott T, McGovern U, Bianchini D, Goodall J, Zafeiriou Z, Williamson CT, Ferraldeschi R, Riisnaes R, Ebbs B, Fowler G, Roda D, Yuan W, Wu YM, Cao X, Brough R, Pemberton H, A'Hern R, Swain A, Kunju LP, Eeles R, Attard G, Lord CJ, Ashworth A, Rubin MA, Knudsen KE, Feng FY, Chinnaiyan AM, Hall E, de Bono JS. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med. 2015 Oct 29;373(18):1697-708. doi: 10.1056/NEJMoa1506859.
2. Cheng HH, Pritchard CC, Boyd T, Nelson PS, Montgomery B. Biallelic Inactivation of BRCA2 in Platinum-sensitive Metastatic Castration-resistant Prostate Cancer. Eur Urol. 2016 Jun;69(6):992-5. doi: 10.1016/j.eururo.2015.11.022. Epub 2015 Dec 24.
3. Beltran H, Eng K, Mosquera JM, Sigaras A, Romanel A, Rennert H, Kossai M, Pauli C, Faltas B, Fontugne J, Park K, Banfelder J, Prandi D, Madhukar N, Zhang T, Padilla J, Greco N, McNary TJ, Herrscher E, Wilkes D, MacDonald TY, Xue H, Vacic V, Emde AK, Oschwald D, Tan AY, Chen Z, Collins C, Gleave ME, Wang Y, Chakravarty D, Schiffman M, Kim R, Campagne F, Robinson BD, Nanus DM, Tagawa ST, Xiang JZ, Smogorzewska A, Demichelis F, Rickman DS, Sboner A, Elemento O, Rubin MA. Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response. JAMA Oncol. 2015 Jul;1(4):466-74. doi: 10.1001/jamaoncol.2015.1313.

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA