PROfound Study TE Articles

Articles

  • ASCO 2020: Health-Related Quality of Life for Olaparib versus Enzalutamide or Abiraterone in mCRPC with Homologous Recombination Repair Gene Alterations: PROfound

    (UroToday.com) The randomized Phase 3 PROfound trial showed that olaparib significantly prolonged radiographic progression-free survival compared with physician’s choice of new hormonal agent (enzalutamide or abiraterone) in men with mCRPC and HRR gene alterations, whose disease had progressed on prior new hormonal agent.1Additionally, olaparib significantly improved time to pain progression in Cohort A. At the 2020 ASCO virtual annual meeting, Antoine Thiery-Vuillemin, MD, PhD, and colleagues reported additional patient-reported outcome measures of health-related quality of life in the overall study population of Cohorts A and B. 
    Published May 29, 2020
  • ASCO 2020: Impact of Olaparib vs Physician’s Choice of New Hormonal Agent on Burden of Pain in mCRPC: PROfound

    (UroToday.com) In the Phase III PROfound study, olaparib significantly improved radiographic progression-free survival (primary endpoint) versus physician’s choice of new hormonal agent (enzalutamide or abiraterone) in patients with mCRPC and homologous recombination repair (HRR) gene alterations.1 In patients with alterations in BRCA1BRCA2 and/or ATM (cohort A), time to pain progression was also significantly improved by olaparib versus physician’s choice of new hormonal agent. At the virtual ASCO 2020 annual meeting, Fred Saad, MD, and colleagues reported additional pain analyses evaluated in the overall study population (cohort A and B).
    Published May 29, 2020
  • ASCO GU 2020: Contemporary Clinical Impact of Genetic and Genomic Testing in Prostate Cancer

    San Francisco, CA (UroToday.com) In this talk, Dr. Elena Castro gave an overview of the genomic landscape of advanced prostate cancer. It has been shown that in over 70% of metastatic castrate-resistant prostate cancer patients there are actionable genetic alterations. 60% of them are in the antigen receptor pathway, 40-60% are in the PI3K-AKT-mTOR pathway, 25% in the DDR, 25% in the cell cycle regulators RB1/CDK and there are others as well.1 
    Published February 14, 2020
  • ASCO GU 2020: Efficacy of Olaparib by Prior Taxane Use in Patients with Metastatic Castration-Resistant Prostate Cancer and Homologous Recombination Repair Gene Alterations: The PROfound Trial

    San Francisco, California (UroToday.com) The PROfound Study is the first positive randomized Phase 3 study in a molecularly-defined population of patients with metastatic castration-resistant prostate cancer (mCRPC). PROfound demonstrated that in men with mCRPC with loss of function alterations in homologous recombination repair (HRR) genes, olaparib significantly prolonged radiographic progression-free survival (rPFS) compared with physician’s choice of new hormonal agent (NHA: abiraterone acetate plus prednisone or enzalutamide). 
    Prior taxane chemotherapy was allowed and was a stratification factor in the study. 

    Multiple therapy options now exist for patients with mCRPC, yet there is a paucity of data on optimal sequence of therapies. In this analysis, the investigators performed a pre-planned analysis to evaluate the efficacy of olaparib in men with HRR-deficient mCRPC based on whether or not they received prior taxane chemotherapy.

    ASCO GU 2020 fig 1 PROfound study design

    Approximately two-thirds of patients on both the olaparib and NHA treatment arms and across both Cohort A (alterations in BRCA1, BRCA2, or ATM) and Cohort A+B (alterations in any of the 15 HRR genes) received taxane chemotherapy prior to treatment in the PROfound Study. Key baseline demographics and clinical characteristics for the cohort are shown in Table 1 (below) broken down by prior taxane chemotherapy in the two treatment arms. In both arms, patients who received prior taxane therapy were younger, had slightly higher rates of visceral disease and measurable disease, and had higher PSA levels.

    ASCO GU 2020 PROfound table 1 baseline demographics
    Subgroup analyses of rPFS (below) favored olaparib over NHA regardless of prior taxane chemotherapy in Cohort A and Cohort A+B. This rPFS benefit reached statistical significance (p < 0.05) in all subgroups except Cohort A+B patients who did not receive prior taxane chemotherapy. Subgroup analysis of overall survival (OS) also favored olaparib over NHA, reaching statistical significance in Cohort A and Cohort A+B patients who received prior taxane chemotherapy, but not in those who didn’t. Two important factors must be considered, however in the OS analysis. First, 82% of patients randomized to the NHA arm crossed over to olaparib at the time of rPFS, which may have confounded the OS analysis. Second, the OS data is only modestly mature with only 41% of events at the time of analysis.

    ASCO GU 2020 PROfound table 2 subgroup analyses

    In an exploratory analysis, the investigators evaluated outcomes by gene subgroup. Patients with BRCA1/2 or CDK12 alterations both showed improved rPFS and OS for olaparib over NHA with or without prior taxane chemotherapy. Better outcomes for olaparib compared to NHA were also observed in patients with ATM alterations who received prior taxane chemotherapy, but not in those who had not. Of note, these results should be interpreted with caution due to small patient numbers and wide confidence intervals.

    The investigators concluded by highlighting that although there are many effective systemic therapies in men with mCRPC, there is a paucity of data regarding optimal sequencing of therapies to guide treatment selection. In the Phase 3 PROfound Study, the benefit of olaparib over NHA was independent of prior taxane use in men with mCRPC with BRCA1, BRCA2, and/or ATM (Cohort A) and in the overall cohort of men with alterations in any of the 15 pre-specified HRR genes (Cohort A+B). These results provide insight into the benefit of olaparib for mCRPC patients regardless of prior taxane chemotherapy.

    Presented by: Johann De Bono, MD, PhD, Regius Professor of Cancer Research at the Institute for Cancer Research and the Royal Marsden Hospital, London, United Kingdom

    Written by: Jacob Berchuck, MD, Medical Oncology Fellow at the Dana-Farber Cancer Institute (Twitter: @jberchuck)  at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California
    Published February 19, 2020
  • ASCO GU 2020: Next-Generation Sequencing (NGS) of Tumor Tissue from >4000 Men with mCRPC: The PROfound Phase III Study Experience

    San Francisco, California (UroToday.com) Metastatic castration-resistant prostate cancer (mCRPC) is a molecularly heterogeneous disease, with between 20 and 25% of patients with mCRPC harboring deleterious alterations in DNA damage repair genes, including those with direct or indirect roles in homologous recombination repair (HRR). These gene alterations, of which BRCA1, BRCA2, and ATM are the most well-characterized, can confer sensitivity to PARP inhibition. The PROfound study showed that olaparib provides a statistically significant improvement in radiographic progression-free survival versus physician’s choice of enzalutamide or abiraterone in mCRPC patients with alterations in genes with a direct or indirect role in the HRR pathway.1 It is the largest study to date to prospectively screen patients with a qualifying alteration of >=1 of 15 prespecified genes by central tumor tissue next-generation sequence testing. At the Prostate Cancer Session at the 2020 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), Maha Hussain reported additional findings of prospective central tumor testing of samples found in the PROfound study.

    Published February 14, 2020
  • EMUC 2020: A New Treatment Paradigm for Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) and BRCA1, BRCA2 or ATM Mutations, The PROfound Study

    (UroToday.com) In an oral presentation in the New Trials Update session at the 12th European Multidisciplinary Congress on Urological Cancers (EMUC), Dr. Karim Fizazi presented a discussion of the results of PROfound Study, Study of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer (PROfound), examining the role of olaparib among patients with metastatic castration-resistant prostate cancer (mCRPC) and DNA defect repair (DDR) mutations.
    Published November 14, 2020
  • ESMO 2019: Central, Prospective Detection of Homologous Recombination Repair Gene Mutations in Tumor Tissue from >4000 Men with mCRPC Screened for the PROfound Study

    Barcelona, Spain (UroToday.com) A proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) have tumor cells harboring homologous recombination repair gene mutations that may confer sensitivity to poly ADP-ribose polymerase (PARP) inhibition1. The PROfound study is a Phase III, randomized, multicenter trial evaluating the efficacy and safety of the PARP inhibitor olaparib versus physician’s choice of enzalutamide or abiraterone acetate in pre-treated metastatic castration-resistant prostate cancer (mCRPC) patients with a qualifying homologous recombination repair gene mutation. Results from this study will be reported later at the European Society for Medical Oncology (ESMO) 2019 Congress. At the ESMO 2019 Prostate Cancer Session, Dr. De Bono and colleagues reported the prevalence of homologous recombination repair gene mutations and co-occurring homologous recombination repair gene mutations in patients screened for PROfound.
    Published September 29, 2019
  • ESMO 2019: Invited Discussant - PROfound: A Phase 3 Study of Olaparib versus Enzalutamide or Abiraterone for mCRPC with Homologous Recombination Repair Gene Alterations

    Barcelona, Spain (UroToday.com) Following oral presentation of the PROfound study of olaparib in metastatic castration-resistant prostate cancer (mCRPC) patients with selected homologous recombination repair defects in their tumors, Dr. Eleni Efstathiou discussed the findings and posed the question of whether this study should be considered practice-changing.

    Published October 1, 2019
  • ESMO 2019: PROfound: Phase 3 Study of Olaparib vs. Enzalutamide or Abiraterone for Metastatic Castration-Resistant Prostate Cancer with Homologous Recombination Repair Gene Alterations

    Barcelona, Spain (UroToday.com) Despite significant progress in systematic therapy, metastatic castration-resistant prostate cancer (mCRPC) continues to be a lethal disease. mCRPC is molecularly heterogeneous, as up to 30% of mCRPC harbor deleterious alterations in DNA damage repair genes, including those with direct and indirect roles in homologous recombination repair. These loss-of-function alterations in homologous recombination repair genes are associated with response to PARP inhibition, of which BRCA1, BRCA2, and ATM are the most well characterized.

    Published October 1, 2019
  • ESMO Virtual Congress 2020: The Final Overall Survival (OS) Analysis From the PROfound Study and IPATential150, Ipatasertib Plus Abiraterone (abi) vs Placebo Plus Abi in Metastatic Castration-Resistant Prostate Cancer (mCRPC) - Invited Discussion

    (UroToday.com) Following the presentations from Johan de Bono on IPATential150, a Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC) and a presentation by Joaquin Mateo on the overall survival (OS) data from the PROfound study, final overall survival (OS) analysis of PROfound: Olaparib vs physician’s choice of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations, Dr. Henrik Grönberg provided the invited discussion of these two presentations.

    Published September 20, 2020
  • ESMO Virtual Congress 2020: Exploring the Impact of Treatment Switching on the Interim Overall Survival Results of the PROfound Study

    (UroToday.com) In the Phase III PROfound study, olaparib leads to significantly longer radiographic progression-free survival compared with physician’s choice of next-generation hormonal agent (control) in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC) and alterations in homologous recombination repair (HRR) genes.1 The study protocol allowed patients in the control arm who experienced radiographic disease progression to switch to olaparib treatment if they also met other prespecified criteria:
    Published September 19, 2020
  • ESMO Virtual Congress 2020: The Final Overall Survival Analysis of the PROfound Study: Olaparib vs Physician’s Choice of Enzalutamide or Abiraterone in Patients with mCRPC and Homologous Recombination Repair Gene Alteration

    (UroToday.com) In 2016, Pritchard and colleagues reported that mutations in DNA-damage repair genes, particularly homologous recombination repair genes, were relatively common among patients with advanced metastatic castration-resistant prostate cancer (mCRPC). This opened the potential for targeted therapy: poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors lead to an accumulation of DNA single-stranded breaks which have particularly profound clinical consequences for patients who lack standard homologous recombination repair mechanisms as a result of mutations in important genes in this pathway, including BRCA1 and BRCA2.
    Published September 20, 2020
  • ESMO Virtual Congress 2020: The Tolerability of Olaparib in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) and Homologous Recombination Repair Gene Alterations: The PROfound Study

    (UroToday.com) In 2016, Pritchard and colleagues reported that mutations in DNA-damage repair genes, particularly homologous recombination repair genes, were relatively common among patients with advanced metastatic castration-resistant prostate cancer (mCRPC). This opened the potential for targeted therapy: poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors lead to an accumulation of DNA single-stranded breaks which have particularly profound clinical consequences for patients who lack standard homologous recombination repair mechanisms as a result of mutations in important genes in this pathway, including BRCA1 and BRCA2. Early data supporting the use of the PARP inhibitor olaparib from the TOPARP-A trial found improvements in progression-free and overall survival in men with heavily pre-treated mCRPC. Similar results were observed in the phase II TOPARP-B trial.
    Published September 17, 2020
  • Olaparib for Metastatic Castration-Resistant Prostate Cancer.

    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.

    Published May 28, 2020
  • Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Can Be Preselected to Maximize Benefit of Olaparib - Maha Hussain


    Reconsidering back-to-back AR-directed therapies: An interview with Maha Hussain, co-principal investigator of the PROfound study.

    Precision medicine and targeted therapy are possible in prostate cancer. Unmet needs have included more focused treatment and novel modes of action to counter resistance to hormonal and cytotoxic therapies. The PROfound sstudy of the PARP inhibitor olaparib in heavily pretreated patients with mCRPC and mutated homologous recombination repair (HRR) genes met its rPFS primary endpoint, and final OS data show significant and clinically meaningful improvement with olaparib versus enzalutamide or abiraterone.

    The greatest benefit was seen in patients with mutated BRCA1, BRAC2, or ATM—genes with a role in HRR. Post-hoc analyses also revealed trends in patients with other mutated HRR genes, which may help physicians when counseling individuals.
    We know that sequential use of androgen receptor (AR)–directed therapies may be limited by cross-resistance. Although there are no data on the optimal treatment sequence in mCRPC, when counseling appropriate patients in the clinic, the PROfound data may prompt consideration of olaparib instead of back-to-back AR-directed therapies.

    Approximately 20% of all patients with mCRPC have DNA repair alterations, mostly commonly mutations in HRR genes such as BRCA1, BRAC2, or ATM. In the PROfound study, patients with mCRPC who progressed on previous treatment with a new hormonal agent and harbored BRCA1, BRCA2, or ATM aberrations (n = 245; cohort A) or other alterations in the HRR pathway (n = 142; cohort B) were randomized 2:1 to receive either olaparib or enzalutamide or abiraterone acetate.  Join Dr. Alicia Morgans, Associate Professor of Medicine and GU Medical Oncologist, as she interviews Dr. Maha Hussain, Professor of Medicine and GU Medical Oncologist; both are at Northwestern University, Chicago, Illinois, USA.

    Official study title: A phase III, open-label, randomized study to assess the efficacy and safety of olaparib (Lynparza™) versus enzalutamide or abiraterone acetate in men with metastatic castration-resistant prostate cancer who have failed prior treatment with a new hormonal agent and have homologous recombination repair gene mutations (PROfound) - NCT02987543

    Biographies:

    Maha Hussain, MD, FACP, FASCO, is the Genevieve Teuton Professor of Medicine in the Division of Hematology-Oncology, Department of Medicine, and the Deputy Director at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine, Chicago, Illinois.

    Alicia Morgans, MD, MPHAssociate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.


    Read the Full Video Transcript

    Alicia Morgans:  Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today a friend and colleague Dr. Maha Hussain, who is a Professor of Medicine and a GU Medical Oncologist also at Northwestern University. Thank you so much for being here with me today, Maha.

    Maha Hussain:  Thank you very much for having me.

    Alicia Morgans:  Wonderful. Well, I wanted to talk with you today about your latest New England Journal of Medicine paper. It sounds like you've had three this year, so it's been a wonderful year and this latest is an update on the PROfound trial, which you also presented at ESMO last year. Really an update on overall survival and some other updates in terms of exploratory analysis. Can you remind us what the PROfound trial was? And then we'll get to talking about what you found.

    Maha Hussain: Sure. So the PROfound trial actually was the first Phase 3 clinical trial that when we designed it, the intent was to apply precision medicine to prostate cancer based on accumulating data regarding the presence of homologous repair defects in prostate cancer. Data stemming from the Stand Up to Cancer. And of course, the TOPARP-A Trial demonstrated a benefit in the subgroup of patients who had again the HRR mutations.

    And so when we designed the trial, we really aimed high. We wanted to pre-select for patients who have the appropriate mutations. The intent was obviously to have this trial address several questions. And at the time of the study design, we actually separated the HRR mutations between the BRCA1, BRCA2, and ATM because this is what I would call the canonical type cohort. And then there was a whole list of other mutations that at least had some suggestive data, but they were not necessarily proven yet with regard to the potential effect of a PARP inhibitor.

    And so the trial was designed with a 2:1 randomization. The intent was to look at radiographic progression-free survival, which was done through a central reviewer for this study. And obviously, there were a series of secondary endpoints, and the overall survival was one of the secondary endpoints. The trial met its primary endpoint of radiographic progression-free survival, which we reported at ESMO last year. And the publication came out in the New England Journal this summer. And then it met several of the secondary endpoints. And of course, the most critical endpoint in the business we're in obviously is overall survival.

    And amazingly again, overall survival was significantly improved, despite the fact that the trial included patients who really were heavily pre-treated. So at a minimum, they had to have at least one AR targeted drug being enza or abi as frontline. But the data clearly, as we published, these patients were heavily pre-treated. Several of them have seen multiple chemotherapies before, some of them have seen both abi and enza.

    And one of the issues that was raised at the time is, is it appropriate to have people see abi, enza, and get into the study and get assigned to a physician choice, abi and enza again, something like that. And at the time of the study design, there were really not many options for these patients and the study was international. So this is essentially a touch better than placebo from that perspective.

    Alicia Morgans:  Well, and that's important because I think one of the most important messages of PROfound has really been that it might not be the best use of our time and our resources to really do these back to back AR directed therapies. But when you were doing this trial, we were in a very different world.

    Maha Hussain:  Exactly, exactly.

    Alicia Morgans:  So can you tell us a little bit about the overall survival findings? So we got findings from cohort A, cohort B as well.

    Maha Hussain: Yes. So basically the overall survival data showed that the cohort A, which is the primary cohort had a significantly longer overall survival. The median was actually 19 months in the olaparib arm and 14.7 months in the control arm. And this is actually despite, again, crossover did occur in the cohorts. But basically, the overall survival, when you look at the risk of death reduction, when you look at the overall population before crossover like just for the primary analysis in the context of cohort A, there was a 31% reduction in the risk of death with the hazard ratio being 0.69.

    If you actually adjust for the crossover, and two-thirds of the patients, in fact, crossed over to olaparib, that hazard ratio goes down to .42. And so clearly a benefit was pretty profound there. It's interesting that the cohort, patients with cohort B, which is the non-BRCA1, 2, and ATM, there was a survival trend, but it was not statistically significant, but the trend was there. And when you adjust for the crossover, the hazard ratio is 0.83. This is clearly highlighting the fact that not all HRR genes are equal. And certainly, there are selective benefits in some of the patients.

    Alicia Morgans: Absolutely. And I think it was so interesting the way that you and the other investigators actually really kind of drill down on that. You had some beautiful exploratory endpoints that you looked at specifically, response by specific alterations. Can you tell us a little more about that?


    Maha Hussain:
      Yeah and I'm more than happy to perhaps share some slides regarding this because obviously going through it one by one is going to be not easy. But definitely, there were some benefits that we are seeing in some cohorts of patients that to my surprise, I thought they were not likely to respond. So clearly the biggest benefit was in the BRCA1, BRCA2, and in the ATM. What's interesting, in the ATM and these are secondary sort of post hoc analyses, is that the patients within the context of the ATM cohort if they've seen Taxotere they have a better chance of responding compared to if they had not.

    So I do think, again, these are what I would say are interesting findings that definitely would need validation, but it actually is okay to use it from a clinical practice. You have a patient in front of you and we have this data. In this case, I think clearly counseling the patient on their choices of treatment is important. But I think if they have an ATM mutation, this is where perhaps one consideration might be to say, maybe Taxotere first, then go to this drug.

    The other cohorts that I think were interesting to see are the different other genes like the CHEK2, there was some suggestion of benefit. Rad, some suggestion of benefit there. And so I think that all in all, there is a trend and I would encourage the audience basically to look at the paper and at the data and then use that as a potential gauge for when they would like to offer their patients the potential for a PARP inhibitor.

    Alicia Morgans:  I think that's a great message because the label is actually broader, certainly than BRCA1 and BRCA2. And also, it can be sort of not the right thing to do to necessarily rely 100% on exploratory analyses that are not powered. But if we have a patient in front of us and we go back to the data, we can at least get a sense of what we might try because there aren't any 100% answers in this.

    Maha Hussain:  Exactly, exactly. And I think that the point here is some judgment has to be used with regard to how best to tackle the management of these patients. And at the end of the day, the vast majority of patients, once you put in the NGS testing for these patients, the bulk of these patients are going to be the BRCA1, BRCA2, and ATM. I think there's going to be a handful at best in our daily practice, patients who have alternative mutations. I would say the biggest one is the CHEK2. Certainly based again, on the CHEK2 and then the CDK12. This is based on obviously the PROfound data, but I have to say in my daily practice, this is something that we see.

    The other thing I want to point out is that the FDA approval actually covered all genes, including cohort B genes, except for a gene that has a long name. I'm sorry. The mutations in the gene are the PPP2R2A. That one actually was allowed in terms of an eligibility criteria.  At the end of the day as more data accumulated and more pre-clinical data accumulated and so on. This is not an HRR gene, and so, a mutation gene. So this is out of the approval panel from the FDA perspective.

    Alicia Morgans:  Thank you for pointing that out. Because I think anytime we have more information coming out particularly regarding whether patients are going to respond to a treatment or not, updates on the label and clarification, it's so important. One thing that folks have talked about as they are thinking about using these drugs, particularly from experience in ovarian cancer and other settings is the development of leukemias and things.

    And I know that you were watching very closely at all of these patients. There was one patient who developed AML. I think this was after essentially, the study follow-up was planned to have ended, but you still included and reported that which I think is very helpful.

    Maha Hussain:  Absolutely. Yeah. And I think safety trumps, in the business we are in. As physicians, safety trumps everything else. And I think you have to report it. There are obviously different reports; however, just by sheer accident, this could have happened. I mean, this is a population, 4,000 patients were screened for this particular trial, albeit, obviously the majority were not included. But I do think that it's important to be mindful of that.

    The other thing I want to highlight is this, is the observation we made on tolerance. And what I think is fascinating is, the patient population and I would really encourage the audience to go look at the eligibility criteria and then look at the patient characteristics. A large number of these patients really had bad disease. They had visceral involvement, they had very high PSAs. The interesting thing is that the age group actually, some of these patients were in the late 80s and early 90s.

    And again, it highlights the feasibility of actually treating those patients in our practice. And so age, again, age is to be respected, but it's not an exclusion factor in terms of offering this. Whereas, if you want to give chemo, you are to really worry a little bit when you have a 92-year-old, for example. So some of these subtleties are I think, important.

    Alicia Morgans:  They are. And also recognizing that so many of these patients were actually exposed to chemo in the past are still being able to tolerate this. That's important as well. So if you had to sum up the data that you've newly presented and now published in the New England Journal, what would your summary be?

    Maha Hussain:  I think the summary would be, as the first thing, the big picture is that precision medicine and targeted therapy are possible in prostate cancer. And that I would encourage all investigators, sponsors, pharma, whomever, to actually look at prostate cancer and look at PROfound and certainly the TRITON trial. It is feasible to do these trials and demonstrate benefits, in fact, if the drug is going to work, but that would be one.

    The second part is, that obviously an exciting part now that we have another drug in the pipeline for managing patients and managing them in a much more personalized matter, similar to, again, the benefit is similar to what is seen in breast cancer, ovarian cancer, and pancreatic cancer. Is it a cure? Of course not. However, I would say that it is remarkable that some of our patients, you may have similar patients on olaparib that have been on treatment for over a year and these are patients that have been heavily pre-treated. So from that perspective, I think it's very exciting.

    I do think that the sky is the limit as to what we can do. And I would love to see us begin to develop combination treatments, investigate additional agents to better personalize the care. And I think from the big picture perspective, understanding even when you're pre-selecting for the HRR mutations, even in the context of the BRACA situation, not everybody responds and the question is why? And so clearly investing in research in this area to better understand collaborative and sort of resistance mechanisms becomes very important.

    Alicia Morgans:  Well, I always appreciate your overarching messages because they're not just summaries of what you found, but where you want to go in the future and certainly encouraging all of us to take those next steps. So thank you again for sharing your take on this fantastic work. Congratulations to you and everyone involved, including the patients for getting this personalized medicine treatment study Phase 3 in prostate cancer actually finished and showing a positive result. Thank you again.

    Maha Hussain:  Thank you very much. And it takes a village as they say. So keep working.

    Published October 16, 2020
  • Significantly Longer Duration of Overall Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer (mCRPC) - PROfound Study Journal Club - Zachary Klaassen and Christopher Wallis

    In this Journal Club, Zachary Klaassen and Christopher Wallis present on the recently published New England Journal of Medicine article Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer,data from the Phase 3 PROfound study.  The primary outcome of the study was radiographic progression-free survival in cohort A, which was focused on BRCA1, BRCA2, and ATM mutant patients which were previously reported.  The results of the final analysis of overall survival had not yet been reported and it is these data being discussed by Drs. Wallis and Klaassen.  They highlight several discussion points from this paper. 

    Biographies:

    Christopher J.D. Wallis, MD, Ph.D., Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee

    Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center


    Read the Full Video Transcript

    Chris Wallis: Hello and thank you for joining us for this UroToday Journal Club. Today, we're talking about a recently published article from the PROfound trial, entitled, "Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer". I'm Chris Wallis, a Fellow in urological oncology at Vanderbilt and with me today is Zach Klaassen, an Assistant Professor at the Medical College of Georgia.

    Here's a citation for the article we will be discussing. Again, this is the overall survival analysis of the PROfound trial led by Dr. Hussain.

    By way of a bit of background, many UroToday readers will know that DNA repair mutations are increasingly important for patients with advanced prostate cancer. And these are important because they offer specific therapeutic targets. And so PARP inhibitors act particularly efficiently in patients who have DNA repair defects. And so this demonstrates the mechanism of these inhibitors. As you can see, stress and reactive oxygen species can cause DNA damage and the standard DNA repair pathway uses PARP as well as recruitment of other DNA repair enzymes to allow DNA repair and ongoing cellular viability. PARP inhibitors interact with the PARP complex and result in a so-called PARP trapping where there is an inability to release PARP, as well as an inability to recruit repair enzymes. And this leads to DNA instability and eventual cell death.

    And so early data first in a Phase II setting looked at 50 patients with extensively pretreated mCRPC who received olaparib. And as you can tell in the rPFS, OS curves down at the bottom right. These metrics were significantly improved with the receipt of olaparib only among patients who had a biomarker positivity, whereas a biomarker negative patients had a significantly worse outcome.

    And so this then led to the TOPARP-B trial, which was an open-label randomized Phase II trial. Again, in heavily pretreated patients with these DNA repair mutations. And this is a bit of a dose-finding study with randomization to 300 or 400 milligrams. And as you can see, overall, the composite response was about 45% with some variation between the dose cohorts of around 39% in the 300 milligrams and 54% in the 400-milligram group. And this led to 400 milligrams being the approach used going forward. And as you can also see by gene subgroups, there are significantly higher response rates in patients with BRCA1 and BRCA2 than other gene mutations.

    And so this led to the rationale for the PROfound trial. And so this study recruited men with metastatic CRPC, who had had prior androgen-signaling agent, that is abiraterone or enzalutamide. Patients had to have one of 15 relevant homologous recombination repair mutations and then the cohort was subsequently stratified with a focus on BRCA1, BRCA2, and ATM mutations. Patients who were enrolled were randomized to receive olaparib as their next line of therapy or an androgen-signaling agent switch. That is a switch from abiraterone to enzalutamide or vice versa. The primary outcome of the study was radiographic progression-free survival in cohort A, which was focused on a BRCA1, BRCA2, and ATM mutant patients.

    And so based on the primary outcome of radiographic progression-free survival here, we see a significant improvement in this metric for patients receiving olaparib compared to an androgen-signaling agent switch. And a secondary outcome on the initial publication for overall survival had fairly immature data. As you can see here, data maturity is only 38%. However, there is evidence of fairly early splitting of the curves, though the effect did not reach significance as the alpha significance threshold here is 0.01 due to alpha splitting.

    We now get to the more mature data looking at overall survival. Again, to review inclusion criteria, these are adult men with mCRPC who have progressed on prior abiraterone or enzalutamide and may or may not have had prior taxane therapy. They had to have one of 15 pre-specified homologous recombination repair defects with a focus on BRCA1, 2, and ATM.

    There was biomarker-driven stratification with this cohort A, among these focused set of genes and cohort B comprising an alteration to any one of the remaining 12 genes. Patients were randomized in a two to one fashion to olaparib versus androgen-axis targeting switch and this was further stratified according to taxane use and measurable disease. Treatment was continued until progression or toxicity and there was crossover allowed for patients receiving abiraterone or enzalutamide who had progression.

    As we already talked about, the primary outcome was rPFS and key secondary outcomes included OS and again, most of these analyses were conducted in cohorts split, but there was also a pooled analysis and there was a pre-specified sensitivity analysis designed to explore the effect of crossover on the apparent benefit of olaparib on overall survival. And this is relevant because crossover was relatively common with upwards of 55% of patients overall and over 60% in cohort A switching to olaparib.

    This just summarizes the study design as we've already discussed. And it's important to focus particularly as we highlighted before, on the alpha splitting on these statistical analyses. And so this utilized a hierarchical analysis strategy with dependence on outcomes in cohort A, that is patients with mutations in BRCA1, 2, and ATM. And so again, there was a hierarchy of outcomes and overall survival in cohort A here being the analysis we are focusing on today. And we've already talked about pre-specified sensitivity analysis for crossover.

    And I will now hand it over to Dr. Klaassen to talk about the results and implications of these data.

    Zach Klaassen: Thanks, Chris. The results in terms of the characteristics at baseline, these are certainly the same from the previous publication as the patients haven't changed. But just by way of review, 4,425 patients were screened, 4,047 had tumors available for testing, of which 2,972 had tumors tested with biomarkers reported, 778 had patients that qualified based on their genetic profile, and among those patients, 387 patients met eligibility and were randomized. You can see here in table one, the baseline characteristics taken from the original paper that the age was basically in the late sixties for the median. There was a preponderance of patients with BRCA2 mutations, as one would expect. You can see here that about one-third of patients had visceral metastatic disease. Most of these patients were of good performance status at ECOG zero or one. And you can see here, the split between the previous enzalutamide only, abiraterone only, or combination of enzalutamide and abiraterone at about 20% in each group.

    Looking a little more into the genetic alterations, I'll draw your attention here to the BRCA2 in cohort A, it was more than half in the olaparib arm and 62% in the control arm. And you can also see that there was a good deal of patients in cohort A that comprised ATM mutation. Almost 40% in the olaparib arm in cohort A and 31.3% in the control arm of cohort A.

    Moving to the results, this paper primarily was focusing on overall survival and they analyzed this in several ways. The first was overall survival in cohort A. This is patients with BRCA1, BRCA2, or ATM mutations. You can see here that in the olaparib arm on the top left, the median overall survival was 19.1 months with a median overall survival in the control arm of 14.7 months. The hazard ratio for death of 0.69 and a 95% confidence interval of 0.50 to 0.97 in the left.

    On the right side, this was patients with regards to crossover adjusted analysis of the overall survival cohort. This is 67% of patients that crossed over. This is a sensitivity analysis on the bottom right and this showed once again, an early split of the curves, favoring olaparib with a hazard ratio for death of 0.42, 95% confidence interval of 0.19 to 0.91. Both of these analyses significantly benefited the olaparib group with regards to overall survival.

    Moving to cohort B, which is the patients with the 12 other genes, not including BRCA1, 2, and ATM, you can see here that there was no difference in overall survival. Once again, on the left, this is the overall survival in cohort B. Median overall survival in the olaparib group was 14.1 months, in the control group, it was 11.5. A hazard ratio of death was 0.96 with a non-significant 95% confidence interval. And we see very similar results in the crossover adjusted analysis in the bottom right of the screen with a hazard ratio of 0.83.

    And finally, what they did was they combined overall survival analysis in cohorts A and B. You see for the olaparib group in the top left the median overall survival was 17.3 months and the median overall survival in the control group was 14 months with a hazard ratio of death non-statistically significantly favoring olaparib. A hazard ratio of 0.79 but 95% confidence interval 0.61 to 1.03. Once again, very comparable results to the primary analysis in terms of the crossover adjusted analysis, the hazard ratio 0.55, 95% confidence interval of 0.29 to 1.06.

    They did several subgroup analyses here as well. What you can see in this plot is a subgroup analysis in cohort A and I will draw your attention to the asterisks as these are the statistically significant findings for overall survival in this group. As we discussed previously, all patients did have a benefit of olaparib versus the control group. Patients that previously received taxane chemotherapy also benefited from olaparib with a hazard ratio of 0.56 and a confidence interval of 0.38 to 0.84. And to summarize the rest of this table, you can see here that ECOG 1 status significantly favored olaparib as did patients that were treated in Europe.

    A similar plot for the overall population. This is a combined cohort A and B, showed that once again, a signal here for patients that had prior taxane chemotherapy with a significant benefit for olaparib with a hazard ratio of 0.66 and a confidence interval 0.49 to 0.91. And finally, the other significant result from this plot is patients benefited from olaparib that had PSA at baseline greater than the median.

    And finally, what they did here was they looked at the results by alterations in single HHR gene deletions. And interestingly enough, this is a strong signal for BRCA2. As you can see here the hazard ratio of 0.59, 95% confidence interval of 0.37 to 0.95. And really this is probably what is driving the majority of these results. As you can see that other than a BRCA1, which had a hazard ratio of 0.42 with a non-significant 95% confidence interval, the rest of these genes either had too few patients to run analyses or were not statistically significant.

    Just to summarize the adverse events in the overall population and compare that to patients at the crossover, to summarize, essentially there were no new signals from the primary analysis to this one. You can see the adverse event, all grades were 96% for olaparib, 88% in the control group, and 93% among those patients that crossed over. The most common adverse events in the olaparib group were anemia at 50% of the patients all grade, nausea 43%, and fatigue and asthenia at 42%. And you can see here that the patients that crossed over had a very comparable adverse event profile as to those that received olaparib upfront.

    Several discussion points from this paper, we saw in PROfound, overall survival analysis that the risk of death was 31% lower with olaparib than with the control therapy, despite a substantial crossover from the control therapy to olaparib. And we found that patients with BRCA1 or BRCA2 alterations, specifically BRCA2, derived the greatest benefit from olaparib with respect to overall survival. And finally, as I mentioned on the previous slide, the trial has found no difference in the safety profile as what was originally reported. This was consistent with the primary analysis and there were no cumulative toxic effects observed.

    In conclusion, PROfound found that among heavily pretreated patients with at least one alteration of BRCA1, BRCA2, or ATM, olaparib led to significantly improved overall survival. As we have shown previously, this was likely driven primarily by the BRCA2 responses. There is an OS benefit for olaparib versus next-generation hormonal agents, despite a substantial crossover from control therapy to olaparib. The previously observed adverse events were consistent despite longer follow-up in the subsequent analysis and ultimately the PROfound control group in this setting likely received substandard care given that there have been previous studies showing that the androgen receptor switch therapy has overall been unsuccessful.

    We thank you for your attention and for attending this UroToday Journal Club.

    Published October 16, 2020
  • SUO 2020: New Second Line Therapy for mCRPC: PARPi: Results from the PROfound Study

    (UroToday.com) At the second prostate cancer session at the 2020 Annual Meeting of the Society of Urologic Oncology (SUO), Dr. Maha Hussain presented the results of the PROfound study, Study of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer (PROfound Study), which demonstrated the superiority of olaparib, a poly (adenosine diphosphate-ribose) polymerase inhibitor, for treatment of metastatic castrate-resistant prostate cancer (mCRPC).

    Published December 4, 2020
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    (UroToday.com) In the second Prostate Cancer session at this year’s Society of Urologic Oncology virtual annual meeting, Dr. Maha Hussain discussed the role of poly ADP ribose polymerase (PARP) inhibitors, particularly olaparib, in metastatic castration-resistant prostate cancer.

    Published December 4, 2020
  • Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer.

    We previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent.

    Published September 20, 2020