Major trial shows breast cancer drug can hit prostate cancer Achilles heel

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Olaparib, a pill lacking the side effects of chemotherapy, can target an Achilles heel in prostate cancers with a weakness in their ability to repair damaged DNA. It is now on the verge of becoming approved as the first genetically targeted treatment for prostate cancer. This precision medicine drug, a type of treatment called a PARP inhibitor which specifically targets cancer cells with faulty DNA repair genes, blocked prostate cancer growth more effectively than the modern targeted hormone treatments abiraterone and enzalutamide.

The final results from the PROfound trial are set to herald the landmark approval of olaparib in prostate cancer in the US and Europe this year. The study was funded by AstraZeneca. A team from The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, alongside colleagues from all around the world including Northwestern University in Chicago, US, studied 387 men with advanced prostate cancer who had alterations in one or more of 15 DNA repair genes. The researchers found that using olaparib in this group of men with faulty DNA repair genes significantly delayed disease progression.

Men with prostate cancers that had faulty BRCA1, BRCA2 or ATM genes benefited the most from receiving olaparib – with their disease taking 7.4 months before it progressed, compared with 3.6 months for those who received enzalutamide and abiraterone.

Men with an alteration in any of the other 12 pre-selected DNA repair genes also benefitted from receiving olaparib. Overall, for men with any of the 15 faulty DNA repair genes who were given olaparib, the length of time before their cancer got worse was 5.8 months on average, compared with 3.5 months with targeted hormonal treatment.
The discovery of abiraterone by The Institute of Cancer Research (ICR), and its development by the ICR and The Royal Marsden, has transformed treatment for men with advanced prostate cancer.

Researchers are excited at the prospect that Olaparib – which the ICR discovered how to genetically target – could be even more effective than abiraterone in selected men with DNA repair mutations.

The overall survival of men with faulty BRCA1, BRCA2 or ATM genes was 19 months on average for those who received olaparib, compared with 15 months for those who received abiraterone or enzalutamide – despite more than 80 per cent of the men who received the targeted hormone treatments switching to olaparib when their cancer progressed and spread. However, longer follow-up will be needed to show a survival improvement conclusively.

The most frequent adverse effects were anaemia and nausea, which have been associated with olaparib in the past. But overall olaparib is a well-tolerated treatment, and much kinder on patients than chemotherapy.

PROfound is the first trial to show how crucial it is to carry out genomic testing in prostate cancer patients. It is vital to identify different patient groups based on their genetics and to tailor treatment accordingly.

Researchers are now hoping to see olaparib become available on the NHS for patients with advanced prostate cancer and faulty DNA repair genes within the next two years. Next, they will look at combining olaparib with other treatments, with the aim of improving outcomes even further.

Study co-leader Professor Johann de Bono, professor of experimental cancer medicine at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said: "Our findings show that Olaparib – a drug which targets an Achilles heel in cancer cells while sparing normal, healthy cells – can outperform targeted hormone treatments in some men with advanced prostate cancer.

"It's exciting to see a drug which is already extending the lives of many women with ovarian and breast cancer now showing such clear benefits in prostate cancer too. I can't wait to see this drug start reaching men who could benefit from it on the NHS — hopefully in the next couple of years. Next, we will be assessing how we can combine olaparib with other treatments, which could help men with prostate cancer and faulty DNA repair genes live even longer."

Professor Paul Workman, CEO of The Institute of Cancer Research, London, said: "It is great to see that this treatment, which we learned how to genetically targeted at the ICR, can successfully hit an Achiles heel in some men with advanced prostate cancer. These landmark findings mean that olaparib is now set to become the first ever genetically targeted drug for the disease. The next step will be to find new ways to combine olaparib with other treatments in order to prevent or overcome drug resistance. It is this kind of research, which aims to target cancer's lethal ability to adapt and evolve, which we will be conducting in our pioneering Centre for Cancer Drug Discovery once it opens later this year."

Abstract
Background: Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate–ribose) polymerase (PARP) inhibition in patients with prostate and other cancers.
Methods: We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2, or ATM; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician’s choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review.

Results: In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib.
Conclusions: In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone.

Authors
Johann de Bono, Joaquin Mateo, Karim Fizazi, Fred Saad, Neal Shore, Shahneen Sandhu, Kim N Chi, Oliver Sartor, Neeraj Agarwal, David Olmos, Antoine Thiery-Vuillemin, Przemyslaw Twardowski, Niven Mehra, Carsten Goessl, Jinyu Kang, Joseph Burgents, Wenting Wu, Alexander Kohlmann, Carrie A Adelman, Maha Hussain

Institute of Cancer Research material

NEJM abstract

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