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Progress and Promise in Prostate Cancer

The PARP Partnering Predicament

Charles Ryan | May 17, 2021

As in politics and history, in drug development, enthusiasm for a concept swings back and forth like a pendulum. Oftentimes when a therapy is new and fresh it is met with responses like “will we simply stop using all other therapies? Is this the one treatment that is going to make future clinical trials unnecessary?” It becomes all about the new thing. The current approaches that have entered this stage are the parp inhibitors (Parpi) and soon, I predict radioligand therapy.

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Dr. Charles J. Ryan, MD

Charles J. Ryan, MD is the B.J. Kennedy Chair in Clinical Medical Oncology at the University of Minnesota and Director of the Division of Hematology, Oncology and Transplantation. He previously held the position of Professor of Clinical Medicine and Urology and the Clinical Program Leader for Genitourinary Medical Oncology at the UCSF Helen Diller Family Comprehensive Cancer Center

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Physician-Scientist Commentaries
Commentaries on Peer-reviewed Journal articles
Written by Jones Nauseef, MD, PhD
Division of Hematology and Medical Oncology at Weill Cornell Medice, and NewYork-Presbyterian Hospital
The time between diagnosis of organ-confined prostate cancer and definitive therapy with radical prostatectomy provides an interval for intervention, with the benefit of pre- (biopsy specimen) and post-intervention (surgical specimen) tissue for comparison.
Written by Jones Nauseef, MD, PhD
Weill Cornell Medicine, NewYork-Presbyterian Hospital
Genotoxic therapies have a long history in a variety of cancers, and recent interest in the poly(ADP-ribose) polymerase (PARP) enzymes as an avenue to command synthetic lethality has led to successes in advanced prostate cancer.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Immune checkpoint blockade (ICB) demonstrated modest clinical activity in patients with metastatic castration-resistant prostate cancer (CRPC). However, it is unclear if radiation therapy synergizes with ICB to enhance the antitumor immune response.
Written by Jones Nauseef, MD, PhD
Division of Hematology and Medical Oncology at Weill Cornell Medice, and NewYork-Presbyterian Hospital
Deletions of PTEN are common in metastatic CRPC, particularly as early driver events, and lead to constitutive activation of PI3K/AKT/mTOR signaling pathways. Such activation not only readily feeds forward to drive cellular proliferation and survival,
Physician-Scientist Review Articles
State of the Evidence Review Articles
Written by Christopher J.D. Wallis, MD, PhD, & Zachary Klaassen, MD, MSc,
June 22, 2021
In spite of the rapid progress and  many exciting advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC) over the past few years, the disease remains incurable with a median overall survival of 12-35 months.
Written by Hari T. Vigneswaran, Andrea Discacciati, Peter H. Gann, Henrik Grönberg, Martin Eklund, Michael R. Abern
August 17, 2020
African American men are known to have nearly twice the incidence of prostate cancer and more than double the risk of prostate cancer mortality compared to Caucasian men.  There are several possible mechanisms for this including risk factors such as lifestyle, diet, genetic risk, inequalities in access to high-quality care, or other socioeconomic factors, however, the contribution of biology in prostate cancer risk is not well understood in this population.
Written by Charles Ryan, MD
June 30, 2020
June 26, 2020, marked the 20th anniversary of the publication of the first working draft from the Human Genome Project. At a special White House event to commemorate the results of this 10-year public effort (it was really more like 50 years since the discovery of DNA, but I digress), then-President Bill Clinton called the project “the most wondrous map ever created by humankind”, and touted its promise to detect, prevent, and treat disease.
Written by Arpit Rao, MBBS and Charles Ryan, MD
June 29, 2020
In this review, we will summarize the current indications for PARP inhibitor monotherapies and combination(s), review data from clinical trials in prostate cancer, discuss management of commonly encountered side effects, and highlight exciting clinical research on expanding the role of PARP inhibitors in prostate cancer.
Written by Veda N. Giri, MD
June 29, 2020
Understanding the role of germline testing in prostate cancer is now critical to urologic and oncology practice for metastatic castration-resistant prostate cancer. Here, we will address who should be considered for germline testing, when germline testing may influence treatment and management, and how to implement germline testing involving provider practices and genetic counseling.
Written by Patrick G. Pilié, MD
June 29, 2020
Men with advanced prostate cancer have a 10-15% risk of carrying a hereditary, or germline, variant in a DNA damage response gene. Pathogenic or deleterious variants in these same DNA damage response genes can also be found at the somatic, or tumor-associated level, in up to 25% of metastatic castrate-resistant prostate cancer.
Written by Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
June 17, 2020
Prostate cancer is a clinically heterogeneous disease with many patients having an indolent course requiring no interventions and others who either present with or progress to metastasis. While underlying dominant driving mutations are not widespread, there have been a number of key genomic mutations that have been consistently identified in prostate cancer patients, across the disease spectrum
Written by Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
April 21, 2020

There are a growing number of treatment options for patients with metastatic castrate-resistant prostate cancer including those targeting the androgen axis (abiraterone acetate plus prednisone and enzalutamide), cytotoxic chemotherapy (docetaxel and cabazitaxel), radiopharmaceuticals (radium-223), and immunotherapeutic approaches (sipuleucel-T).

Written by Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
January 6, 2020

Several trials have recently focused on delineating the optimal radiotherapy fractionation schedule for the primary treatment of prostate cancer. In 2016, efficacy results of the Dutch HYPRO trial were published, assessing hypofractionated radiotherapy compared with conventionally fractionated radiotherapy among patients with intermediate-risk to high-risk T1b-T4NX-N0MX-M0 localized prostate cancer.1

Written by Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
December 10, 2019
Prostate cancer metastases to the bone is a late manifestation of the prostate cancer disease spectrum, often painful for the patient and potentially dangerous in the setting of skeletal-related events. Among prostate cancer patients, the cumulative incidence of bone metastasis at one and five years after diagnosis is 8% and 17%, respectively1.
Written by Hanan Goldberg, MD
November 19, 2019
In the previous review article (“First-line treatment of metastatic castrate-resistant prostate cancer”), metastatic castrate-resistant prostate cancer (mCRPC) and its approved first-line treatment options were elaborated.
Written by Hanan Goldberg, MD
November 19, 2019
In 2019 Prostate cancer (PCa) accounts for nearly 1 in 5 new diagnoses of cancer in men in the USA.1 In the last several years the overall prostate cancer (PCa) incidence rate declined by approximately 7% per year.
Written by Hanan Goldberg MD, Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA
January 22, 2020
Prostate cancer (PCa) is the second most common form of cancer diagnosed in US men. It represents 19% of newly diagnosed cancers, and the third leading cause of cancer death, accounting for an estimated 39,430 deaths in 2018.1
Written by Zachary Klaassen, MD
April 16, 2019
In 2018 in the United States, there will be an estimated 164,690 new cases of prostate cancer (19% of all male cancer incident cases, 1st) and an estimated 29,430 prostate cancer mortalities (9% of all male cancer deaths, 2nd only to lung/bronchus cancer).
Conference Coverage
Conference Highlights Written by Physician-Scientist
Presented by Maha Hussain, MD, FACP, FASCO
In a session at the 2021 APCCC on molecular characterization of both tissue and blood, with a focus on implications for treatment with PARP inhibitors and beyond, Dr. Maha Hussain discussed the role of somatic tumor testing.
Presented by Gerhardt Attard, MD, PhD, FRCP
In this presentation, Dr. Gerhardt Attard discussed the results of abiraterone acetate plus prednisolone (AAP) with or without enzalutamide (ENZ) added to androgen deprivation therapy (ADT) compared to ADT alone for men with high-risk non-metastatic (M0) prostate cancer. This study comprised a combined analysis from two comparisons in the STAMPEDE platform.
Presented by Cora N. Sternberg, MD, FRCP
Following the presentation from Neeraj Agarwal of the results of expanded cohort 6 of the COSMIC-021 Study utilizing cabozantinib + atezolizumab in men with metastatic castration-resistant prostate cancer (mCRPC), Cora Sternberg provided an invited discussion to contextualize these results.
Presented by Shahneen K. Sandhu, MBBS FRACP
In the Proffered Paper Session of the ESMO Annual Congress focusing on prostate cancer, Dr. Shahneen Sandu presented the preliminary results based on an interim analysis of the PRINCE trial assessing the role of 177-Lu-PSMA-617 in combination with pembrolizumab in men with metastatic castration-resistant prostate cancer (mCRPC).
Presented by Neeraj Agarwal, MD 
In the Proffered Paper Session of the ESMO Congress focusing on prostate cancer, Dr. Neeraj Agarwal presented results of the COSMIC-021 cohort 6, examining the role of cabozantinib and atezolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC).
Presented by Michael Morris, MD
In the on-demand poster session of the ESMO Annual Congress, Dr. Morris provided a summary of the PSMAfore trial in progress (NCT04689828). This study examines the role of [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) in taxane-naïve patients with mCRPC.
Presented by Michael Schweizer, MD
In the on-demand poster session of the ESMO Annual Congress, Dr. Schweizer described a single-center phase II trial testing olaparib in combination with Bipolar Androgen Therapy (BAT) for men with metastatic castration-resistant prostate cancer (mCRPC).
Presented by Fred Saad, MD, FRCS

In a podium presentation at the American Urologic Association (AUA) Virtual Annual Meeting, Dr. Fred Saad and colleagues presented an exploratory analysis of the efficacy of olaparib versus either abiraterone or enzalutamide, given a potential difference in the efficacy of NHA sequencing.

 

Presented by Brian Chapin, MD
 The AUA annual meeting included a State-of-the-Art Lecture by Dr. Brian Chapin who discussed personalized medicine in the management of prostate cancer across the patient care continuum.
Presented by Deborah R. Kaye, MD, MS
The AUA annual meeting’s evolving landscape of advanced prostate cancer treatment session included a talk by Dr. Deborah Kaye discussing the role of immunotherapy and PARP inhibitors. Dr. Kaye started by highlighting that there are currently numerous options for systemic treatment of metastatic castration-resistant prostate cancer (mCRPC). 
Presented by Leonard G. Gomella, MD
The AUA annual meeting’s evolving landscape of advanced prostate cancer treatment session included a talk by Dr. Leonard Gomella discussing genetic testing in advanced prostate cancer. Dr. Gomella notes that there have been rapid advances in prostate cancer genetic testing, reflected in changes made to the NCCN guidelines from 2016-2020.
Presented by Silke Gillessen, MD
Silke Gillessen discussed the recently published TheraP1 and VISION2 trials. Dr. Gillessen notes that in the metastatic castration-resistant prostate cancer (mCRPC) setting, we now have several treatment options that offer a survival benefit, including abiraterone, cabazitaxel, docetaxel, enzalutamide, radium-223, sipuleucel-T, olaparib, and now 177Lu-PSMA-617.
Presented by Johann de Bono, MB ChB FRCP MSc Ph.D. FMedSci
Dr. Johann De Bono provides us with an overview of prostate cancer molecular testing, along with guidance on which patients and when we should be obtaining them.
Presented by Gero Kramer, MD
(UroToday.com)  Dr. Gero Kramer reviews the systemic treatment options for metastatic castration-resistant prostate cancer (mCRPC) and highlights some recent developments.
Presented by Michael J. Morris, MD
At the 2021 ASCO Dr. Michael Morris and colleagues reviewed the trial design for a phase III study to determine the clinical benefit of docetaxel versus docetaxel and Radium-223 in patients with mCRPC, the DORA trial.
Presented by Veda Giri, MD
The 2021 ASCO program included a session discussing the application of genomic testing treatments for patients with prostate cancer, including a presentation by Dr. Veda Giri discussing genomic medicine in prostate trials and treatments.
Presented by Todd Morgan, MD
In the American Urologic Association (AUA) Course of Choice Lecture at this year’s Southeast Section of the American Urologic Association Virtual Annual Meeting, Dr. Morgan discussed the role of genetic testing in prostate cancer across the spectrum of the disease natural history from early detection to the treatment of localized disease and castration-resistant prostate cancer (CRPC).
Presented by Adam Kessel, medical student at the University of Utah
In this poster, the authors presented efficacy and safety results from a phase 2 single-center randomized study of enzalutamide monotherapy versus combination enzalutamide and radium-223 in progressive metatstatic castration-resistant prostate cancer (mCRPC)
Presented by Peter Nelson, MD
In this panel discussion, the presenters answered questions from the audience on the prior session, which are summarized here.
Presented by Arpit Rao, MD, MBBS,
Preclinical studies have demonstrated potential synthetic lethality between androgen receptor signaling inhibition and PARP inhibition, which led to the investigation of these two drugs in combination. The phase 1 RAMP study was designed to investigate potential drug-drug interactions and pharmacokinetics in genomically unselected patients as well as safety with the combination of enzalutamide and rucaparib. 
Presented by Michael J. Morris, MD
The case presented was that of a 54-year-old man with an extensive family history of cancer. His mother died from ovarian cancer, his father had prostate cancer and died of colon cancer, his brother developed kidney and prostate cancer, and his sister had breast and ovarian cancer.
Presented by Tamer Khashab, MD
In this study, Dr. Khashab presented genomic data derived from a retrospective analysis of patients treated at a community-focused academic healthcare system in Texas that serves a higher percentage of Hispanic and African American patients with prostate cancer. 
Presented by Evan Yu, MD
Following Dr. Morgan’s presentation during the Understanding the Evolving Treatment Landscape in Prostate Cancer: How to Leverage the Latest Advances and Strategies to Optimize Patient Outcomes session at the 2020 Society of Urologic Oncology (SUO) annual meeting, 
Presented by Maha H.A. Hussain, MD, FACP, FASCO
AT the 2020 SUO annual meeting, Dr. Hussain discussed the role of PARP inhibitors, particularly Olaparib, in mCRPC. Dr. Hussain began by reviewing the rationale for targeting PARP-1 in advanced prostate cancer given its implicated role in many aspects of prostate cancer including its role in mediating DNA repair response to alkylating agents,
Presented by Kara N. Maxwell, MD, Ph.D.
In the second Prostate Cancer session at this year’s Society of Urologic Oncology (SUO) virtual annual meeting, Dr. Kara Maxwell provided an overview of biomarkers for patients with advanced prostate cancer. While many urologists are familiar with and may use, tissue-based biomarkers in early disease, there is an increasing number of actionable biomarkers in advanced disease.
Presented by Karim Fizazi, MD, Ph.D
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.
Presented by Gerhardt Attard, MD, PhD
At the European Multidisciplinary Congress on Urological Cancers (EMUC) 2020 virtual meeting, the Individualized Approaches in Advanced Prostate Cancer session featured a presentation by Dr. Gerhardt Attard discussing when and how to test germline and mutations in patients.
Presented by Emanuela Romano, MD
Docetaxel is an approved therapy for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) that may work in part by inducing immunogenic cell death of prostate cancer cells.
Presented by Cora N. Sternberg, MD
At the 2020 European Society for Medical Oncology Virtual Congress (ESMO), Dr. Ben Tran presented AMG 160, a half-life extended, PSMA-targeted, bispecific T-cell engager (BiTE®) for patients with metastatic castration-resistant prostate cancer (mCRPC) (NCT03792841).
Presented by Ben Tran, MBBS, FRACP
There is an urgency to develop therapies with novel mechanisms of action to treat prostate cancers resistant to chemohormonal and radiation therapies. Unfortunately, to date, immune therapies have offered limited efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC).
Presented by Joaquin Mateo, MD
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).
Presented by Johann de Bono, MB ChB FRCP MSc Ph.D. FMedSci
There has been a rapid change in the past few years for patients with advanced prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC). It was in this disease space that change first began in earnest with the introduction of docetaxel on the basis of TAX-327.
Presented by Mihaela Aldea, MD, PhD
Up to 30% of metastatic castration-resistant prostate cancer (mCRPC) men harbor DNA damage repair defects and may benefit from poly-ADP ribose polymerase (PARP) inhibitors after abiraterone/enzalutamide and docetaxel failure. Cabazitaxel was recently shown to improve overall survival in this population
Presented by Matthew Rettig, MD
Dr. Matt Rettig from the University of California Los Angeles’s Jonsson Comprehensive Cancer Center and the West Los Angeles VA Medical Center presented a plenary talk discussing the use of biomarkers to select patients for immune checkpoint blockade with PD-1/PD-L1 inhibitors.
Presented by Alison Birtle, MD
(UroToday.com) Dr. Alison Birtle gave a talk on the ever-changing treatment paradigm of advanced prostate cancer (Figure 1). Metastatic castrate-resistant prostate cancer (mCRPC) is a lethal disease with huge heterogeneity. The same patient can have coexistence of androgen receptor-dependent and independent tumor cells.
Presented by Neeraj Agarwal, MD,
While highly prevalent genetic changes have yet to be identified in patients with advanced prostate cancer, alterations in DNA mismatch repair (MMR), also known as DNA damage repair (DDR), are increasingly common as patients progress through the natural history of the disease process.
Presented by Fred Saad, MD, FRCS
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.
Presented by Daniel George, MD
San Francisco, CA (UroToday.co) The addition of bicalutamide to ongoing ADT has been approved for patients with hormone sensitive prostate cancer. This drug is also commonly
Presented by Alicia Morgans, MD, MPH
San Francisco, California (UroToday.com) Multiple treatment options exist for men with metastatic prostate cancer, and guidelines do not define optimal treatment selection
Presented by Karim Fizazi, MD, PhD
San Francisco, California (UroToday.com) During the Rapid Abstract Session A: Prostate Cancer session at the Annual ASCO GU 2020 meeting in San Francisco, CA,
Presented by Joaquin Mateo, MD, PhD
Washington, DC (UroToday.com) To conclude the Society of Urologic Oncology (SUO) 2019 advanced prostate cancer session, Dr. Joaquin Mateo provided an overview
Presented by Joaquin Mateo, MD, PhD
Washington, DC (UroToday.com)  At the Advanced Prostate Cancer session at the 2019 Annual Meeting of the Society for Urologic Oncology, Dr. Joaquin Mateo presented an overview
Presented by Maha Hussain, MD
Barcelona, Spain (UroToday.com) Despite significant progress in systematic therapy, metastatic castration-resistant prostate cancer (mCRPC) continues to be a lethal disease.
Presented by Eleni Efstathiou, MD, PhD
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.
Presented by Ronald De Wit, MD, PhD
Barcelona, Spain (UroToday.com) Multiple therapeutic options have been approved for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC), including the second-generation anti-androgens abiraterone and enzalutamide, and chemotherapy with docetaxel or cabazitaxel.
Presented by Maha Hussain, MD
Barcelona, Spain (UroToday.com) Though significant progress has been made in elucidating molecular alterations in metastatic castration-resistant prostate cancer (mCRPC), no biomarker-selected targeted therapeutic options have existed in this disease until today. Dr. Hussain and colleagues presented an analysis of the PROfound study
Presented by Nicholas James, MBBS, PhD
Barcelona, Spain (UroToday.com) Multiple studies have shown the efficacy of docetaxel in metastatic hormone-sensitive and castration-resistant prostate cancer, though there is ongoing debate regarding the impact that metastatic disease burden has on docetaxel use in the hormone-sensitive setting. 
Presented by Karim Fizazi, MD, PhD
Barcelona, Spain (UroToday.com) Relative to other solid tumors, prostate cancer is viewed as an immunologically “cold” tumor with less robust responses to immunotherapy than other diseases such as melanoma or lung cancer.
Presented by Wassim Abida, MD, PhD
Barcelona, Spain (UroToday.com) Rucaparib is a PARP inhibitor and has shown antitumor activity in patients with mCRPC and a deleterious DNA damage repair-deficient gene alteration. 
Presented by Matthew R. Smith, MD, PhD
Barcelona, Spain (UroToday.com) Patients with metastatic castration-resistant prostate cancer (mCRPC) and disease progression after androgen receptor (AR) targeted therapy and taxane-based chemotherapy have a poor prognosis and few options for treatment.
Presented by Robert Van Soest, MD, PhD
Barcelona, Spain (UroToday.com) Dr. Robert Van Soest presented on the recent advances in the treatment of castrate-resistant prostate cancer (CRPC). The current therapeutic options in metastatic hormone-sensitive prostate cancer (mHSPC), and the 1st and 2nd treatment lines of metastatic CRPC. Recently, there is randomized prospective data comparing various treatments in metastatic CRPC patients. One example is a study comparing cabazitaxel to abiraterone or enzalutamide in metastatic CRPC patients
Presented by Noel Clarke, MD
Barcelona, Spain (UroToday.com) PARP inhibitors have been increasingly recognized for their potential therapeutic role in patients with advanced prostate cancer, particularly in the setting of DNA repair defects. Prior work by Dr. Clarke and colleagues demonstrated, in a phase II clinical trial, that olaparib in combination with abiraterone significantly prolonged radiologic progression-free survival compared with abiraterone alone) in patients with mCRPC in the second-line metastatic setting who received prior docetaxel.1
Presented by Christopher P. Evans, MD, FACS
Barcelona, Spain (UroToday.com) Review of some of the most important studies in the castrate-resistant prostate cancer space published in the past year. First, from ESMO 2018, in a phase 3 randomized controlled trial, radium 223 with abiraterone (ERA 223) did not demonstrate improved symptomatic skeletal-related event-free or overall survival compared to abiraterone with placebo. Clinical fractures were more common in the abiraterone and radium group. Based on the data from the study, the use of radium 223 in combination with abiraterone was not recommended. 
Presented by Kim N. Chi, MD
San Francisco, CA (UroToday.com) The LATITUDE study,1 published in July 2017, was a phase III randomized, clinical trial that evaluated the efficacy of abiraterone acetate and prednisone with androgen deprivation therapy (ADT) in men with newly-diagnosed, castration sensitive, metastatic prostate cancer. 1199 men were randomized to receive ADT with abiraterone and prednisone, versus ADT with dual placebos.
Presented by David F. Jarrard, MD
San Francisco, CA (UroToday.com) David F. Jarrard, MD provided an update on the CRPC AUA guideline amendment and highlights, the six index patients associated with the CRPC guidelines assists in clinical decision making, representing the most common clinical scenarios that are encountered in clinical practice. Guideline statements are developed to provide a rational basis for treatment based on currently available published data. The purpose of this guideline amendment is essentially to update current management of index patient 1: asymptomatic non-metastatic CRPC.