Prostate cancer is deadly. It is the second leading cause of cancer death among men in America. This year, over 33,000 men will die of prostate cancer in the United States. Moreover, it is the most common cancer among men in the United States. In fact, one in nine Americans will develop prostate cancer in their lifetime.
As an oncologist that treats prostate cancer patients, this is an exciting time because knowledge is exploding in prostate cancer with cutting-edge information, advances in molecular biology, and precision care treatments for our patients. This was evident at the 2020 European Society of Medical Oncology Virtual Meeting when I had a chance to interview Dr. Neeraj Agarwal.
The following is an interview between Dr. Chandler Park, President of the Kentucky Society of Clinical Oncology (ASCO); and Dr. Neeraj Agarwal, MD, Professor of Medicine
Huntsman Cancer Institute (HCI) Presidential Endowed Chair of Cancer Research
Co-leader, HCI Experimental Therapeutics Program (CCSG Program) Director, Center of Investigational Therapeutics Director, Genitourinary Oncology Program.
Dr. Chandler Park: Dr. Agarwal, congratulations to you and your PROfound study group for your landmark prostate cancer study in the NEJM.
Dr. Neeraj Agarwal: Thank you Dr. Park. Great to talk to you.
Dr. Park: Dr. Agarwal, as one of the leading thought leaders in prostate cancer, there were some interesting studies at ESMO 2020, most notably, the Presidential Symposium with the final overall survival analysis of the PROFound study. What are your thoughts on this study?
Dr. Agarwal: The PROfound trial is the first-ever positive large phase 3 trial in patients with metastatic castrate-resistant prostate cancer where patients were selected based on an underlying biomarker.
Eligibility: In this trial, patients who had progressive metastatic castrate-resistant prostate cancer and who have had disease progression on novel hormonal therapy with abiraterone or enzalutamide or both (20% had both). Prior disease progression on chemotherapy with docetaxel was also allowed, but not required, and about 65% had received docetaxel.
Design of the trial: A randomized, controlled trial where patients with progressive metastatic caster-resistant prostate cancer were randomized in a two-to-one fashion for treatment with a novel hormonal therapy with abiraterone or enzalutamide versus treatment with olaparib, a PARPi inhibitor. There were two cohorts: Cohort A had patients with BRCA1, BRCA2, or an ATM mutation, while Cohort B included men with mutations in 12 other DNA repair genes. The primary endpoint was radiographic progression-free survival in Cohort A, but there were many other secondary endpoints such as radiographic progression-free survival in all patients, time-to-pain progression, and overall survival in Cohort A. One important aspect of this trial was that patients in the control arm were allowed to cross over to the olaparib arm upon disease progression on the abiraterone or enzalutamide.
Results: Three hundred eighty-five patients positive for biomarkers were randomized to olaparib versus a novel hormonal therapy. There were 245 patients in Cohort A and 143 patients in Cohort B. Overall survival (OS) was significantly improved on treatment with olaparib compared to those who received novel abiraterone or enzalutamide. The median OS on the hormonal therapy arm was fourteen-and-a-half months, and this improved by four-and-a-half months to almost 19 months on treatment with olaparib, with a hazard ratio of 0.69, which means an almost 30% reduced risk of death with olaparib. It is worth noting that 67% of patients crossed over from the hormonal therapy control arm to olaparib, as allowed by the protocol at the time of disease progression. So if you statistically adjust for this crossover, the overall survival benefit with olaparib was even further improved with a hazard ratio going down to 0.42, which translates into a 60% reduction in risk of death with olaparib.
Side effects: Talking about the side effects, there were no new safety signals. The most clinically relevant that is grade ¾ side effects were anemia and nausea which we all know can be easily handled in the clinic with supportive measures.
Final message: I like to conclude by saying that approval of olaparib and also another PARP inhibitor, rucaparib is a very welcome step in the area of precision medicine in advanced prostate cancer, which basically means for the first time in the history of medicine, we have a targeted drug available for our patients with metastatic castrate-resistant prostate cancer who are positive for a genomic biomarker. Hence there is no reason for any of us to not perform genomics profiling (of the tumor tissue or of circulating tumor DNA) in patients with advanced prostate cancer, and inform our patients about the survival benefit with olaparib.
Dr. Park: Great analysis. Dr. Agarwal, it is now the standard of care for all patients with metastatic prostate cancer to undergo genetic testing for germline mutations. What do you think about somatic genomic testing of the prostate cancer biopsy?
Dr. Agarwal: Everyone should have somatic genomic testing, as about half of these patients do not have any germline mutations. In other words, doing only germline testing will only detect these mutations in half of the patients.
Dr. Park: What somatic mutations would you consider for treatment?
Dr. Agarwal: The FDA approved olaparib for patients with all these mutations after the primary endpoint of radiographic progression-free survival was met in cohort A and all patients. Having said that, one of the genes, PPP2R2A, is no longer considered a homologous recombination repair gene, and olaparib should not be offered to patients with a mutation in this gene. Also, I am still not convinced about the benefit of olaparib in those with ATM Mutation and would like to see more data before making up my mind.
Dr. Park: In August 2020, the FDA approved liquid biopsies from Guardant and Foundation Medicine. How do you incorporate them in your practice?
Dr. Agarwal: Any of these available. I perform liquid biopsy testing on pretty much all patients as tumor tissue is often collected many years before or may not even be available. Many patients are either not eligible or not willing to go for a fresh tumor biopsy. Liquid biopsy is a very good option for these patients.
Dr. Park: We had another study that discussed a specific somatic gene mutation known as PTEN loss. What are your thoughts on the phase III IPATENIAL150 trial
Dr. Agarwal: Not ready for prime time. Co-primary endpoints: investigator-assessed rPFS (PCWG3 criteria) in ITT and PTEN-loss (by IHC) populations. First, rPFS in the ITT population was not significantly improved. Even in the PTEN loss (by IHC) population, PFS was improved by two months, which was statistically significant. In my view, we need to wait for the OS results before making a firm opinion on the results of this trial and the applicability of these results in my patients.
Dr. Park: Lastly, I was very excited to learn about the potential for immunotherapy in a subgroup of prostate cancer patients. What are your early thoughts on the Cosmic 021 study with Cabozantinib and Atezolizumab.
Dr. Agarwal: Very promising results so far where there are very limited treatment options. In this patient population who had “progressive” measurable soft tissue disease on treatment with abiraterone, enzalutamide, or both, the objective response rate of 33% is very promising. An additional 47% of patients attained stability of disease. Put together, this translates into 80% disease control rate. No new safety signals were seen. A phase 3 trial is currently accruing patients in the US and many other countries.
Dr. Park: Thank you Dr. Agarwal for the great interview. Looking forward to catching up at a future ASCO meeting.
My personal thoughts — after reviewing all of the current data —
- It is now standard of care for all patients with metastatic prostate cancer to undergo genetic testing for germline mutations and somatic mutation testing based on the PROFound study and the similar Triton 2 study. In May 2020, the FDA approved Olaparib and Rucaparib for specific germline mutations. We now have 2 FDA-approved medications that can help our patients with specific germline genetic mutations.
- Liquid biopsy for metastatic prostate cancer is a standard of care for our patients. Many prostate cancer patients have prostate biopsies that are many years old. Studies have shown that tissues more than two years old may not be viable for somatic testing. Also, hormone-sensitive prostate cancer is not the same as metastatic castrate-resistant prostate cancer, the biology of these two cancers are different. If a metastatic, castrate-resistant prostate cancer patient has liver, lung, or peritoneal metastatic disease, I will still consider tissue biopsy, especially if they have a liver disease to rule out small cell/neuroendocrine variants. However, if the patient progressed on enzalutamide, apalutamide, darolutamide, or docetaxel with a bone-only disease, I will go with a liquid biopsy.
- For patients at later lines of treatment (post-third-line Cabizitaxel based on CARD trial, I will consider checkpoint inhibitors if they have specific biomarkers such as CDK12, MSI High, or even high tumor mutation burden based on tissue agnostic FDA approval in June 2020.
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