Genetic gene mutations: opening new therapeutic avenues in metastatic prostate cancer

Selected by the American Society of Clinical Oncology (ASCO) to first outing during its Genitourinary Cancers Symposium, Translating Evidence to Multidisciplinary Care, February 8 – 10 (San Francisco, USA), Joaquin Mateo, Principal Investigator of VHIO’s recently created Prostate Cancer Translational Research Group, has revealed findings from a retrospective and international study showing for the first time that patients with inherited DNA repair mutations benefit from standard therapies in a similar way to other metastatic prostate cancer patients.

Timed to coincide with Joaquin Mateo’s presentation today at this week’s ASCO meeting, these results have just published online ahead of print in the prestigious journal European Urology.

Given that standard therapies traditionally target the hormonal basis of prostate cancer – as opposed to genetic mutation – the team sought to evidence whether patients with metastatic prostate cancer with identified DNA-repair gene mutations, typically found in one out of every ten of these patients, could derive similar benefit from treatment with standard of care therapies. In so doing, they aimed to establish the prognostic and predictive value of these alterations towards a more personalized stratification of patients.

Between 2005 – 2015, the most common cancer for men was prostate cancer with an estimated 1.6 million cases. Recent findings suggest that while it is relatively rare for prostate cancer to spread in the body, metastatic and aggressive prostate cancer is on the rise.

“While prostate tumors are more generally slow-growing than other cancers, the reality in Spain alone is that this disease claims the lives of 6,000 individuals every year. Translational studies aimed at better identifying which patients would most likely benefit from both standard therapies as well as novel anti-cancer approaches are critical if we are to ultimately improve outcomes for patients with metastatic disease”, observes Joaquin, first author of the study.

Until quite recently, prostate cancer was considered to be exclusively dependent on male androgens fuelling prostate cancer cell growth, and the majority of anti-cancer therapies have thus focused on tackling this tumor type from this angle. Current research is rapidly transforming the way in which prostate cancer is both considered and managed, paving the way for more effective and tailored treatment approaches.

Previous findings published in Cell* in 2015 showed that between 20-25% of patients with metastatic prostate cancer had DNA-repair related mutations as well as BRCA mutations, or similar. In 2016, Mateo and colleagues evidenced that DNA-repair gene mutations are found inherited in one out of every ten men with metastatic prostate cancer. This discovery, published in The New England Journal of Medicine**, has since placed these mutations firmly under the lens in efforts aimed at benefiting an increasing number of these patients.

Additional research has therefore centered on showing whether individuals with these identified mutations could better respond to other treatments. Clinical findings also reported by Joaquin and co-collaborators from the Institute of Cancer Research – Royal Marsden NHS Foundation Trust (London, UK), revealed that some of these patients responded to PARP inhibitors, which are already approved in the case of metastatic breast cancer and ovarian cancer in carriers of mutations in BRCA. This discovery has since led to several currently ongoing international clinical trials in prostate cancer. The next step was to analyse treatment response in these patients to establish whether this inherited genetic variation affects the efficacy of therapy.

In this latest study, results were analysed for a total of 390 metastatic prostate cancer patients with DNA-repair gene mutations to assess response to standard treatments. Findings indicate that patients with BRCA mutations respond to these therapies in a similar way to other patients with metastatic prostate cancer patients without these mutations. Overall survival and disease-free progression were therefore comparable and no significant differences in response rate to first-line treatment were observed. In addition, a trend toward greater overall survival was noted in those patients with mutations who had participated in studies with PARP inhibitors or platinum-based therapy.

“Since this cohort of patients is the first with long-term data available on the response to post-therapy with PARP inhibitors and platinum-based agents, our research also marks an important first. We are seeing that patients with these mutations not only benefit from standard treatments, but may also have additional therapeutic options available”, explains Joaquin.

“While our data are still preliminary, I believe that we have every reason to be optimistic about these initial results. Importantly, with several trials with PARP Inhibitors for prostate cancer currently underway at VHIO, new clinical data to emerge from these studies will hopefully further support the use of these inhibitors in the treatment of our patients”, he concludes.

Joining forces with VHIO’s Genitourinary, CNS Tumors, Sarcoma & Cancer of Unknown Primary Site Group Cancer led by Joan Carles, also located within the Vall d´Hebron Barcelona Hospital Campus, Joaquin’s Prostate Cancer Translational Research Group will pioneer research aimed at translating prostate cancer genotypes into phenotypes and a clinically-relevant classification of the disease. These teams will also seek to build a precision medicine core for prostate cancer patients.

His group’s expertise, combined with that of Joan Carles, will accelerate the translation of the use of PARP inhibitors as a more effective therapy for metastatic prostate cancer patients to the clinic. Currently open clinical studies performed at VHIO, matched to the molecular alterations and specificities detected in individual patients, are possible thanks to its renowned prescreening program, pioneered by VHIO’s Cancer Genomics and Molecular Oncology Groups, led by Ana Vivancos and Paolo Nuciforo, respectively.

For more information please contact: Amanda Wren, Director of Communications, Vall d’Hebron Institute of Oncology (VHIO), Email: awren@vhio.net.

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References:

* Robinson D, Van Allen EM, Wu Y-M, Schultz N, Lonigro R, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015;161(5):1215–28.

** Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53.

Imagen: Joaquin Mateo, investigador principal del Grupo de Investigación Translacional en Cáncer de Próstata del VHIO