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Christopher Wallis: Hello, and thank you for joining us for UroToday Journal Club discussion. Today we're talking about a paper entitled, Patient-Reported Outcomes with Olaparib Plus Abiraterone versus Placebo Plus Abiraterone for Metastatic Castration-Resistant prostate Cancer: A Randomized, Double-Blind Phase II Trial. I'm Chris Wallis, assistant professor in the Division of Urology and with me today Zach Klaassen, an assistant professor in the Division of Urology at the Medical College of Georgia. You can see here the citation for this recent publication in Lancet Oncology led by Dr. Saad and Dr. Clarke.

Prostate cancer is the second most common cancer and fifth largest cause of cancer death in men. Approximately 14% men in unscreened populations present with metastatic disease, and after, 40% of patients who present with non-metastatic disease may progress to have evidence of metastases showing in their natural history. Despite numerous treatment options that have been developed in the mCSPC and nmCRPC disease space, nearly all patients develop castration resistance and metastatic castration-resistant disease is the final common pathway towards prostate cancer-related mortality. There have been numerous approvals of new agents in mCRPC, dating back to docetaxel in 2004, and in general, all of these have been used to date only in monotherapy settings.

Among the more recent of these are the PARP inhibitors, and so you can see here data from two publications from the PROfound trial, first highlighting rPFS and then OS showing a statistically significant survival benefit for the use of olaparib compared to an NHA switch in patients who had progressed after prior abiraterone enzalutamide. You can see that this is larger in those patients who are in cohort 1 or BRCA1, BRCA2, and ATM-positive.

The question then is, can we combine these agents with established treatment approaches in mCRPC, namely next generation hormonal agents? And there's rationalities may have a synergistic effect, and this is two-fold. First, PARP is involved in androgen receptor signaling, therefore, co-inhibition of PARP may actually enhance treatments that target the AR pathway. Additionally, and sort of on the flip side, next generation AR signaling agents may actually inhibit homologous recombination repair gene transcription, and thus this induced HR deficiency may lead to increased sensitivity to PARP or this is so-called BRCA-ness.

This was assessed in this phase II trial, the first results of which were published a few years ago, and that's in Oncology and led by Dr. Clarke. This showed, as you can see highlighted here, that in this randomized comparison, the use of the combined approach with olaparib plus abiraterone proved rPFS outcomes compared to abiraterone or with placebo.

This led to the phase III PROpel trial, which moved this even earlier as first-line therapy and mCRPC, again demonstrating rPFS benefit. However, efficacy and safety alone are insufficient to capture the patient experience and really understand the benefit of novel treatment approaches. Patient-reported outcome metrics are key in this regard, and so the authors examine patient-reported outcomes as a predefined exploratory endpoint in this phase II trial of olaparib plus abiraterone versus abiraterone alone. This trial has been previously published, but in short, it's a double-blind, randomized phase II trial comparing abiraterone with olaparib to abiraterone with placebo aa second-line therapy for patients with mCRPC who have already received docetaxel.

All patients had to be adults with histologically or cytologically confirmed prostate cancer, metastatic disease based on conventional imaging, and castration-resistant disease based on Prostate Cancer Working Group criteria with progression while on ADT and castration levels of testosterone. All patients had to have prior docetaxel and could have had one other line of therapy prior to inclusion, however, no prior ARATs or PARP were allowed.

Men were randomized in a 1:1 fashion to abiraterone with olaparib or abiraterone with placebo. These were given in standard doses. Notably, there was an initial dose-escalation run in with olaparib at 200 milligrams twice daily, which was uptight treated to 300 milligrams, and this is what was used in the randomized portion of the trial. There was no stratification performed and treatment at the time of progression was at the investigator discretion. The primary outcome of the study, as we've highlighted in previously published data, was imaging-based progression-free survival. However, one of the key secondary endpoints was health related quality of life. Notably, patients had assessment every 12 weeks with imaging, blood samples every 4 weeks initially, and had questionnaires, as we'll see highlighted here.

Patients had the patient-reported outcome metrics performed to assess a variety of endpoints including the effect of treatment on pain, health-related quality of life, health state utility, and other cancer related symptoms.

These were done using the BPI-SF, FACT-P, and EQ-5D-5L surveys. To briefly summarize, BPI-SF provides a measurement of 15 different measures of assessing pain severity and interference, and the authors focused on the worst pain metrics. The FACT-P score has four subscales, which focus on physical, emotional, functional, and social or family wellbeing, as well as a specific 12-item prostate cancer symptom subscale. Finally, the EQ-5D-5L is a descriptive system assessing five different dimensions including mobility, self-care, usual activities, pain or discomfort, and anxiety or depression, as well as a visual analog scale. The patients enrolled in the trial completed surveys at baseline and then at weeks 4, 8, and 12, and then every 12 weeks thereafter until treatment discontinuation.

The authors had pre-specified patient-reported outcome metrics that they wish to analyze, including the change from baseline and BPI-SF worst pain score, the single item worst bone pain, the FACT-P treatment outcome index score, the time to deterioration and worst pain and worst bone pain scores, and the EQ-5D-5L health status utility index.

Notably, the study was not powered for these outcomes and was instead power based on the rPFS data, so all analyses in this are exploratory. Analyses were performed in the full analysis subset in compliance for assessment and each visit was assessed. Changes from baseline for each outcome were assessed using mixed models for repeated measures with the visit, treatment by visit interaction, baseline score, and score by visit interaction included in the models as fixed effects. The time to deterioration was assessed using the Kaplan-Meier method and log-rank test. I'm going to hand it over to Zach to walk us through the results of this analysis.

Zachary Klaassen: Thanks so much, Chris, for that great introduction. This is the trial profile as listed here on the right, you can see that there was 171 patients that were assessed for eligibility. Ultimately, 142 are randomly assigned, including 71 to the olaparib plus abiraterone arm and 71 to the placebo plus abiraterone arm. Ultimately, 46 patients out of 71 discontinued therapy in the olaparib arm and 47 discontinued therapy in the placebo arm.

This is the baseline characteristics. As you can see here on the right, the median age was 70 for the patients receiving olaparib compared to 67 for those receiving placebo. The majority, at 94%, of patients were white, and even in this pretreated cohort, the majority of patients were ECOG 0 or 1. Interestingly, you can see with regards to PSA at the time of study entry, it was quite higher in the olaparib plus abiraterone arm, at 86 compared to 47 in the placebo plus abiraterone arm.

In terms of extensive disease, this was well balanced between the groups. 46% had bone only disease, 11-15% had soft tissue only disease. Number of metastasis all also a little bit different between these two groups. You can see that for those with two to four bone metastases, 34% in the olaparib arm and 51% in the placebo arm. With regards to five to nine bone metastases, 55% in the olaparib arm and 35% in the placebo arm. Looking at the HRR mutation status balance between the groups with roughly 15% of patients in arm having an HR mutation. With regards to previous therapy, all patients had prior docetaxel and roughly 14% had previous cabazitaxel.

This is the least-squares mean change from baseline with the BPI-SF worst pain metric and you can see the mean baseline BPI-SF worse pain for olaparib plus abiraterone was 3.5 compared to 3.3 for placebo plus abiraterone. If you look at the graph to the left, there was no difference over time between placebo and olaparib, with olaparib the red line and placebo plus abiraterone the blue line. This is the least-squares mean change from baseline with regards to worst bone pain. Again, there was no difference over time and you can see the mean baseline worse pain was 2.8 for olaparib plus abiraterone and 2.5 for placebo plus abiraterone.

This is the time to deterioration and pain looking at the BPI -SF worse pain metric. Again, we see a median time to deterioration in the olaparib arm of 8.1 months compared to 7.6 months in the placebo arm, with a non-statistically significant hazard ratio of 0.9 and 95% confidence interval of 0.62 to 1.32. This is the same time to deterioration and pain Kaplan-Meier for worse bone pain. Again, no difference between these arms. Median time to deterioration was 8.7 months for olaparib plus abiraterone and 8.2 months for placebo plus abiraterone, with a hazard ratio of 0.85 and a 95% confidence interval 0.59 to 1.22.

This is the least-squares mean change in FACT-P total score from baseline per visit, and we can see that the change in FACT-P total score from baseline for olaparib plus abiraterone, was -0.60, for placebo plus abiraterone, was -2.09, with a difference between these arms of 1.48, which was not statistically significant with the p-value of 0.59. And again, with looking at the graph, you can see there's no difference over time between the two groups with the FACT-P total score metric.

This is the time to deterioration in FACT-P score. Median time to deterioration for olaparib plus abiraterone almost 5.7 months and was 6.0 months for placebo plus abiraterone, with a hazard ratio of 0.97 and a confidence interval of 0.68 to 1.40. Again, not statistically significant.

Several discussion points from this analysis. This is the first analysis of health-related quality of life and disease-related symptoms for patients unstratified by H HRR deficiencies receiving a PARP inhibitor and a novel hormonal agent. Patients with mCRPC did not experience a significant difference in health-related quality of life or pain when olaparib was combined with abiraterone. There was no negative effective combination therapy on pain and no negative effect on combination therapy for health-related quality of life. Combination therapy did not affect time to deterioration and pain or health-related quality of life or time to improvement in pain or health-related quality of life.

The authors did note several limitations of this study, including that all of the patient reported outcome analyses were exploratory, as Chris mentioned, and the study was not powered for pain and health-related quality of life endpoints. Additionally, the patient numbers were low in this phase II trial, with some imbalances, as I highlighted, in the patient characteristics between these two groups.

In conclusion, in this pre-specified exploratory analyses, there was no significant difference in pain or health-related quality of life when olaparib was added to abiraterone. These results suggest that the improved survival benefits observe when combining olaparib with abiraterone does not result in different health-related quality life compared with placebo plus abiraterone. Phase III trials such as PROpel are certainly required to confirm these results. We thank you very much for your attention and we hope you enjoyed the UroToday Journal Club discussion.