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Urologic Oncology With Christopher Wallis, MD, PhD, FRCSC

Urology

Dr. Wallis is a urologic oncologist at the University of Toronto and Mount Sinai Hospital/University Health Network. He completed his Society of Urologic Oncology-accredited fellowship training at Vanderbilt University Medical Center. His clinical work and research are focused on the care of patients with prostate, kidney, bladder, and testis cancer.

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Hello all,

Today I want to walk you through one of the hot topics of this month’s the UroGPO Fall 2023 National Conference, hosted by Specialty Networks, namely, the role of intensified combination therapy using an androgen receptor signalling inhibitor (ARSI) with a PARP inhibitor (PARPi) as first-line treatment for mCRPC. We’ve seen a number of large trials in this space presented in major meeting and subsequently published over the last few years. This spring gave us the approval of three combinations – abiraterone and niraparib, enzalutamide and talazoparib, and abiraterone and olaparib.

Philosophically, there has been much debate about how we should use this treatment paradigm in practice – two of the studies were designed as “all-comer” studies while the other took a biomarker driven approach. Approvals have been similarly confusing – while the FDA adopted a (relatively strict) biomarker driven approach, the EMA was much more liberal.

In this email, I’m highlighting the most recent publications of these studies, along with meta-analyses and some commentary that I’ve found helpful in shaping my practice in this space. Hope it helps you come to some clarity!

-c
Christopher JD Wallis, MD PhD FRCSC

Articles
  • Mashup Score: 0
    Poly(adenosine diphosphate-ribose) polymerase inhibitor combinations in first-line metastatic castrate-resistant prostate cancer setting: a systematic review and meta-analysis - 1 year(s) ago

    To compare radiographic progression-free survival (rPFS), overall survival (OS), and treatment-emergent adverse events (TEAEs) among patients with metastatic castrate-resistant prostate cancer (mCRPC) receiving a combination of first-line poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) plus androgen receptor axis-targeted agents (ARAT) vs placebo/ARAT.

    Source: BJUI
    Categories: Latest Headlines, Urology
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      walliscjd

      To try to make sense of all of these data, we put together a meta-analysis which was published over the summer in BJU International. Based on data available at that time, we found that the addition of a PARPi to ARAT in the first-line mCRPC setting is associated with rPFS benefits across subgroups, with the greatest magnitude of benefit in biomarker positive, BRCA1/2 mutated patients. Overall survival benefits remain inconsistent irrespective of HRRm status, with significant increases in Grade ≥3 TEAEs, particularly anaemia. Thus, we suggested this combined approach be selectively offered to HRRm patients, preferentially BRCA1/2m.

  • Mashup Score: 0
    TALAPRO-2: First-Line Talazoparib/Enzalutamide Excels in Patients With BRCA-Mutated mCRPC - 1 year(s) ago

    The phase 3 TALAPRO-2 trial showed that adding talazoparib to enzalutamide in the first-line setting significantly reduced the risk of progression or death by 55% among patients with HRR-deficient mCRPC, meeting the primary endpoint.

    Source: ascopubs.org
    Categories: Latest Headlines, Urology
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       In addition to the all-comer cohort highlighted above, the TALAPRO-2 trial also enrolled a biomarker positive cohort. While the data are not yet published, they were presented at ASCO 2023 by Karim Fizazi and demonstrated a significant benefit to the use of talazoparib plus enzalutamide in this population.

  • Mashup Score: 0
    Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial - 1 year(s) ago

    Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR).

    Source: The Lancet
    Categories: Latest Headlines, Urology
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      walliscjd

      The third trial to report in this space was TALAPRO-2. Dr. Aggarwal presented the all-comers cohort from this trial at ASCO-GU this spring with the manuscript (highlighted here) subsequently published. Designed in much the same way as PROpel, this cohort of the TALAPRO-2 trial demonstrated significantly improved radiographic progression-free survival among all-comers with mCRPC receiving first-line treatment with talazoparib plus enzalutamide, compared to enzalutamide. To date, overall survival data remain immature.

  • Mashup Score: 1
    Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer - 1 year(s) ago

    Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies.

    Source: ascopubs.org
    Categories: Latest Headlines, Urology
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      Published over the summer, the MAGNITUDE trial used a biomarker driven approach with separate cohorts of biomarker positive and negative patients. The biomarker negative cohort was closed early due to futility. However, the results published in the Journal of Clinical Oncology showed significantly improved radiographic progression-free survival among patients with homologous recombination repair defects who received abiraterone and niraparib in combination, as compared to abiraterone alone.

  • Mashup Score: 2
    Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial - 1 year(s) ago

    PROpel met its primary endpoint showing statistically significant improvement in radiographic progression-free survival with olaparib plus abiraterone versus placebo plus abiraterone in patients with first-line metastatic castration-resistant prostate cancer (mCRPC) unselected by homologous recombination repair mutation (HRRm) status, with benefit observed in all prespecified subgroups. Here we report the final prespecified overall survival analysis.

    Source: The Lancet
    Categories: Latest Headlines, Urology
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      This past month, we saw the publication of the final, pre-specified analysis of the PROpel study, assessing abiraterone and olaparib in combination. This study was the first to be presented and published and has led the push of evidence in this disease space. This analysis showed that, in the all-comer population, overall survival was not significantly different between patients receiving abiraterone and olaparib in combination compared to abiraterone alone as first-line mCRPC treatment. These data clearly influenced the FDAs approval in a biomarker driven approach.