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.


Subsequently, the phase III PROfound study demonstrated improved progression-free survival for men with homologous recombination repair-deficient mCRPC following treatment with abiraterone acetate or enzalutamide administered at the time of non-metastatic castrate-resistant prostate cancer or at the time of metastatic castrate-sensitive prostate cancer who received olaparib, as compared to a switch in novel oral androgen-axis targeting agent. These data were presented and published in spring 2020.

In a poster presentation at this year’s European Society of Medical Oncology (ESMO) 2020 Virtual Annual Meeting, Dr. Roubaud presented data assessing the safety and tolerability of olaparib from the PROfound study. This represents a key secondary endpoint of the PROfound study. The authors again emphasized that within the PROfound study schema, patients were randomized to olaparib (300mg BID) or placebo in a 2:1 fashion with treatment continued until disease progression or unacceptable toxicity.

In this safety analysis, 386 patients were included, of whom 25 received olaparib and 130 received control.

The authors noted that the vast majority of adverse events in this study population were grade 1 or grade 2. Anemia, nausea, asthenia, and decreased appetite were the most common events.

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Notably, the vast majority of these events had symptom onset within 3 months of initiating treatment, with the median time to adverse event onset being less than 2 months for nearly all of the four most common adverse events. Duration of these events last between 1 and 4 months.

As may be expected by the generally low severity of these adverse events (grade 1 and 2), most were managed with supportive case or dose modification. Treatment discontinuation was required in 18% of patients receiving olaparib, with anemia being the most common reason for treatment discontinuation.

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Interestingly, pulmonary embolism was more common among patients receiving olaparib (4% vs 1% among controls) for reasons that are not entirely clear.

In conclusion, the authors noted that the most common adverse events experienced by patients in the PROfound study were anemia, nausea, asthenia, and decreased appetite. Adverse events were generally grade 1 or 2, occurred within the first 3 months, and could be managed with supportive care, dose reduction, and dose interruption.

Presented by: Guilhem Roubaud, MD, Medical Oncologist, Institut Bergonié, Bordeaux, France

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center (@WallisCJD on Twitter) at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020 


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