Research Abstract

I am presently Associate Professor at Harvard Medical School and Director of Bladder Cancer Program at Genitourinary Oncology Program of Beth Israel Deaconess Medical Center. I am the former Director of the Bladder Cancer Center at Dana-Farber Cancer Institute. My clinical expertise focuses on urological diseases, particularly prostate, bladder and kidney cancer. I have extensive experience treating prostate and bladder cancer patients and have been a key investigator in several trials conducted in this patient population.

Since 1996 and within the EORTC, I was the chairman of the Advanced Bladder Cancer Committee, and study Chair and co-chair for 30987 and 30986 studies. To confirm the results of triple therapy with TCG, we designed the 30987 study, the largest study conducted in advanced bladder cancer comparing CG versus TCG (JCO 2012). Looking for second-line options in patients failing platinum, we reported the phase III study of vinflunine versus placebo in 2009 that led to the approval of vinflunine in the European Union (JCO 2009). Based on this study, the role of prognostic factors in second-line treatment was described (JCO 2010). In the area of new therapeutic targets, we reported the study of Sunitinib in front line therapy. In collaboration with Jonathan Rosenberg (DFCI), we analyzed the molecular profile of the Spanish bladder cancer patient series (ASCO2011). Currently and based on the findings of PI3K mutations, we are studying in preclinical models the efficacy of PI3K and TOR1-2 inhibitor drugs in bladder cancer cell lines.

I have been involved in, and led urothelial cancer trials for over 15 years in Europe in the EORTC GU Group. I focused on the development of new systemic treatment for bladder cancers, and the search for prognostic factors and potential therapeutic targets. I developed the MCAVI schedule for unfit patients (Cancer 1992) as the control arm for the EORTC30986 study versus Gemcitabine-Carbo (JCO 2010). Subsequently, I reported the superiority of cisplatin versus carboplatin in the randomized trial of MVAC (methotrexate, vinblastine, adriamycin and cisplatinum) versus MCAVI (methotrexate, carboplatin and vinblastine) (Cancer 1997). To improve the combination of CG (Cisplatin/Gemcitabine), we conducted an investigational phase I/II study with the three drug regimen of paclitaxel, cisplatin and gemcitabine (JCO 2000).

In 2001 we reported the feasibility study of the combination of carboplatin/gemcitabine (EurJCancer) which

was used as the experimental arm to design the randomized study in patients unfit for platinum EORTC 30986 (JCO 2012). Subsequently, the 30987 study was designed; the largest study conducted in advanced bladder cancer comparing CG versus TCG (JCO 2012). Looking for second-line options in patients failing platinum, we reported the phase III study of vinflunine versus placebo in 2009 that led to the approval of vinflunine in the European Union (JCO 2009).

I have been involved in the development of immunotherapy in bladder cancer since its inception. I participated on the two phase I trials with atezolizumab (Nature. 2014 and with pembrolizumab (Lancet Oncol. 2017) and the phase II atezolizumab (Lancet 2016) that lead to the FDA approval and that I also co-authored. Along the same line, I have contributed to the development of these agents in unfit bladder cancer patients (Lancet 2017). One of my most important contributions in bladder cancer has been to be the Chair and lead investigator of the phase III randomized study of immunotherapy (pembrolizumab) versus chemotherapy. This is a landmark trial showing survival superiority for immunotherapy versus chemotherapy. The results were published in the NEJM (Bellmunt J, N Engl J Med. 2017). I am also the PI of the study Imvigor 010 (adjuvant atezolizumab in bladder cancer). Results will be presented at ASCO 2020.

Treatment of non-muscle invasive bladder cancer (NMIBC) has changed little in 20 years. Despite initial therapy with induction Bacillus Calmette-Guerin (BCG), High-risk NMIBC (HR-NMIBC) is highly prone to recurrence (40%), and some patients will experience progression to muscle-invasive disease or metastatic disease (21%). Less than half of patients who have persistent or recurrent NMIBC after a single induction course of BCG will respond to a second induction course of BCG. However, regardless of response to re-induction, patients still remain at risk for subsequent relapse. At this point, the most established therapy is radical cystectomy, which entails substantial morbidity and mortality. Identification of new clinically relevant therapeutic targets and predictive biomarkers is critical to improve outcomes for this disease.

There are a growing number of combination trials with PARP inhibitor plus PD-1/PD-L1 antibody therapy in different diseases, including urothelial cancer, in muscle-invasive and advanced urothelial cancer. NMIBC is an area where immune checkpoint inhibitors (ICIs) are promising (KN-057 trial presented at ASCO GU 2018, resulting in FDA approval for pembrolizumab for BCG-unresponsive NMIBC) and where PARP inhibitors deserve exploration. Research at our Lab is showing that pathologic DNA repair alterations are present at high frequency, as high as 60%, supporting that combination trials with PARP inhibitor plus PD-1/PD-L1 antibody therapy deserve further exploration. Our hypothesis is that increased DNA damage by olaparib will complement anti-tumor activity of immune checkpoint blocking antibody (ICI) durvalumab, among NMIBC patients. The goal of our proposed research is to demonstrate a superiority in event-free survival (EFS) rate with durvalumab and olaparib versus BCG as maintenance.