Mitchell O. Finkelstein (high school research intern), presented this presentation during the 31st Annual International Prostate Cancer Update in July 2021, in Snowbird, Utah.
Read MoreDaniel P. Petrylak, MD, Director of Genitourinary Oncology, Professor of Medicine and Urology, Co-Leader of Cancer Signaling Networks, and Co-Director of the Signal Transduction Program at Yale University Cancer Center in New Haven, Connecticut, discusses the future of lutetium-based trials. He argues in favor of the use of lutetium-177 (177Lu)–PSMA-617 earlier in the treatment cycle for prostate cancer. Dr. Petrylak examines the disease states for non-castrate and castration-resistant prostate cancer (CRPC) and concludes that there is a better hazard ratio in terms of survival when drugs such as abiraterone acetate, enzalutamide, apalutamide, and docetaxel are used earlier in disease progression. Dr. Petrylak posits that it makes sense, then, to use 177Lu-PSMA-617 in the earlier setting as well. He discusses the scientific rationale for earlier use of 177Lu-PSMA-617, including the fact that fewer genomic alterations exist in earlier disease stages, alterations that may later lead to resistance to radiation therapy (RT) and to other treatments. Dr. Petrylak explains that the expression of prostate-specific membrane antigen (PSMA) increases with androgen deprivation therapy (ADT), potentially leading to better patient outcomes. Additionally, ADT inhibits DNA strand break repair and this can synergize with RT. He then cites a trial being designed to examine the earlier use of 177Lu-PSMA-617 in men with untreated or minimally-treated metastatic hormone-sensitive prostate cancer (mHSPC), who will be randomized on a 1:1 basis and given 177Lu-PSMA-617 for six cycles plus best standard of care or given best standard of care. Dr. Petrylak explains the study design as well as its primary endpoint (the time from randomization to the date of radiographic progression-free survival) and secondary endpoints. He then discusses dose, administration, and standard of care. Dr. Petrylak concludes by asserting that this is an exciting trial and urges his colleagues to participate. Beyond this current trial, Dr. Petrylak theorizes about potential combinations with Lutetium-based compounds, including immunotherapy, citing the abscopal effect; poly adenosine diphosphate-ribose polymerase (PARP) inhibitors, though this may be limited by cytopenias; as well as the implementation of next-generation antiandrogens, which can upregulate PSMA. Dr. Petrylak concludes by calling this data exciting and asserting it will be a basis for future clinical trials.
Read MoreSteven E. Finkelstein, MD, FACRO, a radiation oncologist with Florida Cancer Affiliates in Panama City, Florida, discusses the role of androgen deprivation therapy (ADT) with radiation therapy (RT) in patients with prostate cancer. Dr. Finkelstein first discusses the definitive setting, explaining optimal durations for the addition of ADT to RT under various circumstances. For example, when local control with RT alone is good, ADT is never given; when the risk of local failure is high, ADT is given for 3-6 months as a radiation sensitizer; and when the risk of distant disease is high, ADT treatment is given for 2-3 years. Dr. Finkelstein goes on to illustrate data that show ADT does not improve survival in men receiving RT for low-risk disease, short-term ADT improves survival in men receiving RT for intermediate-risk disease, and ADT was effective in improving survival for patients with “modern” high- and intermediate-risk disease. Dr. Finkelstein discusses dose escalation in RT and cites an ongoing study examining 1520 patients who received either 79.2 Gy alone or 79.2 Gy plus 6 months of ADT, with the primary endpoint being overall survival (OS), asserting that the study will be seminal once the results have been published. He then reviews the current summary recommendations in the definitive setting: for low-risk (NCCN definition) and low-intermediate-risk patients, the recommendation is surveillance, brachytherapy (BT), or external beam radiation therapy (EBRT) with no recommendation for ADT; for high-intermediate risk patients, the recommendation is EBRT +/- BT with 4-6 months of ADT (GnRH agonist); and for high-risk (NCCN definition) patients, the recommendation is EBRT +/- BT with 24 months of ADT(GnRH agonist). Dr. Finkelstein then introduces Kevin D. Healey, a research intern and medical student level two, who delivers the second part of the presentation, focusing on the salvage setting. Mr. Healey presents research from the GETUG-AFU 16 trial, examining short-term ADT combined with RT as salvage treatment after radical prostatectomy for prostate cancer: a 112-month follow-up of a phase 3, randomized trial. He concludes that salvage RT combined with short-term ADT significantly reduced the risk of biochemical or clinical progression and death compared with salvage RT alone. Further, the results of the trial confirm the efficacy of ADT plus RT as salvage treatment in patients with increasing PSA concentration after radical prostatectomy for prostate cancer. Dr. Finkelstein then concludes the presentation with the current summary recommendations for the salvage setting, including adding a 6-month course of ADT (LHRHa) to salvage RT in men with no or minimal comorbidity, given the near halving of progression and the possible reduction in mortality due to prostate cancer.
Read MoreRobert E. Reiter, MD, the Bing Professor of Urology and Molecular Biology and Director of the Prostate Cancer Treatment and Research Program at the David Geffen School of Medicine at the University of California, Los Angeles, discusses oligometastatic prostate cancer, explaining how to treat it and the long-term benefits of doing so. He describes oligometastatic prostate cancer (PCa) as an intermediate disease state characterized by limited disease (1-5 lesions). Dr. Reiter then shows evidence of the oligometastatic disease state through data suggesting that if you can identify patients with oligometastases and have a treatment plan for them then you can have a great impact on their OS. He discusses the impact of imaging on defining oligometastases through a study on the distribution of lesions in men with BCR, finding that as PSA increases so does the range of areas that PSMA detects lesions within; a UCLA study comparing PSMA and conventional imaging (CI), finding that 21% of cases showed non-concordance between the two methods for node-positive PCa; and a pathologic assessment of PSMA PET in the detection of nodal disease, showing that PSMA PET still misses small positive lymph nodes in about 20% of patients. Dr. Reiter continues with a review of clinical trials in Oligometastatic disease. He shows data from the SABR-COMET trial suggesting that treating oligometastatic disease in many different cancer types did improve overall survival and progression-free survival in the long term, and the STOMP trial, finding that administration of SABR to patients with oligometastatic disease defined by choline has a beneficial effect on PCa outcomes. Dr. Reiter concludes with the ORIOLE study which suggests that patients in whom all lesions can be found and treated will have significantly better outcomes than others, and a study on curative-intent metastasis-directed therapies for molecularly-defined oligorecurrent PCa using PSMA finding that median time to progression could be extended to 17 months.
Read MoreDaniel P. Petrylak, MD, Director of Genitourinary Oncology, Professor of Medicine and Urology, Co-Leader of Cancer Signaling Networks, and Co-Director of the Signal Transduction Program at Yale University Cancer Center in New Haven, Connecticut, launches his talk with some background on radium-223 before reviewing the ALpharadin in SYMptomatic Prostate CAncer (ALSYMPCA) trial, including study design, patient demographics, and baseline characteristics. He presents an updated analysis of overall survival (OS) which showed a benefit of 3.6 months compared with a placebo. Dr. Petrylak posits that it makes sense to combine radiation and immunotherapy because of potential synergism, citing the abscopal effect. He then refers to a trial, A Phase Ib Study of Atezolizumab with Radium-223 Dichloride in Men with Metastatic Castration-Resistant Prostate Cancer, addressing the three arms of the trial and presenting survival data, including a waterfall plot demonstrating prostate-specific antigen (PSA) and a very modest objective response rate. Dr. Petrylak discusses the evaluation of the abscopal effect, with trial data not showing PDL1 expression increasing after radium-223; in terms of the abscopal effect, Dr. Petrylak concludes, “it’s just not there.” He further concludes that the trial findings were disappointing. Dr. Petrylak then turns his focus to research on radium-223 with abiraterone/prednisone that found increased patient bone fractures. This finding led to an urgent safety letter being issued, mandating the use of bone-protective agent (BPAs) for at least six weeks before the first injection of radium-223 to reduce fractures. Dr. Petrylak cites data from the EORTC 1333/PEACE III trial which confirms that risk of fractures was well controlled when patients with metastatic castration-resistant prostate cancer (mCRPC) received BPAs, emphasizing the importance of compliance with the BSA recommendations. Dr. Petrylak moves on to cite a study examining radium-223 with chemotherapy (docetaxel) showing significant PSA declines. This research is now part of the DORA trial, which is still recruiting patients nationally. Dr. Petrylak addresses radium-223 dosing, citing investigational trials involving higher doses of radium-223 and extended dosing cycles. He concludes that data support the current regimen of six cycles of radium-223 at the standard dose as the optimal regimen in mCRPC. Dr. Petrylak concludes his discussion by emphasizing that combination trials with docetaxel are ongoing.
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