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Zachary Klaassen: Hello, and welcome to this UroToday discussion of the NCCN guidelines, looking at prostate cancer, which was updated in February of 2021. Today, we will be discussing chemotherapy, immunotherapy, and targeted therapy in advanced prostate cancer. My name is Zach Klaassen, I'm an Assistant Professor in the Division of Urology at The Medical College of Georgia. And with me today is Chris Wallis, who's an Assistant Professor in the Division of Urology at The University of Toronto.

For patients with mCRPC with or without symptoms, recent data has dramatically expanded the number of available treatment options. As you can see here, this is a very busy and complex table from the NCCN guidelines, showing the options available based on prior receipt of docetaxel and prior novel hormone therapy.

So in this section specifically looking at chemotherapy, immunotherapy, and targeted therapy, this is broken down into six different treatment options. And today we will be focusing on sipuleucel-T, pembrolizumab, and the treatment in DNA-repair gene mutations, specifically the PARP inhibitors.

So first, sipuleucel-T was approved by the FDA in April of 2010. And this is known as an autologous cancer vaccine, whereby the collection of white blood cell fraction-containing antigen-presenting cells are collected from each patient. And then these cells are exposed to prostatic acid phosphatase-granulocyte macrophage colony-stimulating factor. And once this process is complete, these cells are re-infused into the patient.

The key trial that led to the FDA approval for sipuleucel-T is the IMPACT phase three trial, which was published in the New England Journal of Medicine in 2010. The impact trial had 512 mCRPC patients that were minimally or asymptomatic, which were randomized two to one to the sipuleucel-T versus placebo. The primary endpoint for this study was overall survival. You can see the Kaplan-Meier curve for this endpoint on the right with the sip-T group having a 22% reduction in risk of death versus placebo with a hazard ratio of 0.78 and a 95% confidence interval of 0.61 to 0.98. This correlated with a 4.1 improvement in the median overall survival, at 25.8 months in the sip-T group and 21.7 months in the placebo group.

Recently in 2019 in cancer was the publication of the PROCEED Registry, which looked at the treatment of mCRPC patients with sip-T. This study looked at 1,976 patients with a median follow-up of 46.6 months and median overall survival for those receiving sip-T of 30.7 months and a 95% confidence interval of 28.6 to 32.2 months.

In terms of recommendations by the NCCN guidelines, sip-T is a category one preferred option for certain patients with mCRPC in the first-line setting. And the panel specifically prefers sip-T to be used as initial therapy for asymptomatic or minimally symptomatic patients with mCRPC. They do mention that it is an option for second-line treatments but do caution that usual markers of benefit that we use in the clinics such as PSA decline or improvement imaging are not seen in those receiving sipuleucel-T. Of note, the benefit has not been reported in patients with visceral metastases, so it is not recommended for these patients. It is also not recommended for patients with small cell or neuroendocrine prostate cancer.

Moving on to pembrolizumab. Pembrolizumab was approved by the FDA in May of 2017 for unresectable or metastatic MSI-high or mismatch repair deficient solid tumors who have progressed on prior treatment and who have no satisfactory alternative treatment options. The approval by the FDA was based on the treatment of 149 patients among five clinical studies involving MSI-high and MMR deficient tumors of which 90 patients had colorectal cancer, 59 had non-colorectal cancer, of which two of these patients had metastatic CRPC. The objective response rate in these combined studies was 40%.

Specifically to the treatment of pembrolizumab in metastatic CRPC is the KEYNOTE-028 trial, which was a phase 1B trial of 23 patients, of which 74% of these patients had greater than or equal to two prior therapies for metastatic disease. This trial found an objective response rate of 17.4%, including four partial responses and eight patients that had stable disease. As you can see on the right on the waterfall plot, 10 out of 21 evaluable patients had a reduction in tumor size from baseline. Of note, 61% of patients had adverse events of which 17% were grade three or four adverse events.

Next is the KEYNOTE-199 trial, which was published in the Journal of Clinical Oncology in 2020. This was a phase two trial of 258 patients that was broken down into three cohorts, as you see listed here. So cohort one, which had 133 patients that were PD-L1 positive, cohort two at 66 patients that were PD-L1 negative, and cohort three had 59 patients with bone-predominant disease plus-minus PD-L1 expression. And the primary endpoint was the objective response rate in cohorts one and two, with cohort one having an objective response rate of 5% and cohort two, an objective response rate of 3%.

On the right, you can see the radiographic progression-free survival Kaplan-Meier curve broken down by cohort, with cohorts one and three having a median rPFS of around just under three months and cohort two just over four months. The response durability in this trial was 1.9 to 21.8 months.

In terms of side effects or pembrolizumab, the most common adverse events are fatigue, pruritus, diarrhea, anorexia, constipation, nausea, rash, fever, cough, dyspnea, and musculoskeletal pain. And pembrolizumab may also be associated with immune-mediated side effects, such as colitis, hepatitis, endocrinopathies, pneumonitis, and nephritis.

In terms of panel recommendations for pembrolizumab, the panel supports the use of pembrolizumab in patients with MSI-high or dMMR mCRPC whose disease has progressed through at least one line of systemic therapy for M1 CRPC. And this is a category 2B recommendation. The prevalence of MMR deficiency in mCRPC is roughly 2% to 5% and testing can be performed using DNA testing or immunohistochemistry. Importantly, if a tumor is MSI-high or dMMR, if this is identified in the tumor, the panel recommends referral for genetic counseling for consideration of germline testing and screening for Lynch syndrome.

I will now pass it over to Chris who will take us through some exciting trials with regards to the PARP inhibitors.

Christopher Wallis: Thanks, Zach. The last portion of this section of the NCCN guidelines looks at treatment options for patients with DNA repair gene mutations, and notably the PARP inhibitors. And so to briefly summarize, these are oral agents that exert their clinical activity through the concept of synthetic lethality in which the agent acts to trap PARP and prevent homologous recombination and mediated DNA repair. And so there is synthetic lethality, which is selective to cells that have homologous recombination repair deficiencies. Currently, there are two PARP inhibitors that are approved for use in prostate cancer, namely olaparib and rucaparib.

The data for olaparib comes from the PROfound trial, which is a phase three randomized controlled trial comparing olaparib and the physician's choice of abiraterone or enzalutamide among patients with mCRPC who had progressed on at least one of the novel hormonal agents, as well as up to one prior taxane therapy. Patients underwent biomarker-based screening and had to have one of 15 somatic or germline homologous recombination repair mutations. Patients were then divided into two cohorts. Cohort A comprising BRCA1/BRCA2 or ATM and cohort B comprising the remaining genes. In cohort A, the primary endpoint was radiographic progression-free survival, which demonstrated significantly improved outcomes for patients who received olaparib. You can see the Kaplan-Meier curve to the right of the screen here.

An ongoing follow-up of the PROfound cohort assessing overall survival was presented subsequently and demonstrated again in cohort A that there is improved overall survival among patients who received olaparib compared to a switch to the abiraterone or enzalutamide, an alternative that had not previously been used. And this was observed in spite of significant crossover rates.

As a result, olaparib was FDA approved in May 2020 for patients with mCRPC who have deleterious germline or somatic homologous recombination repair mutations in one of 14 genes and who previously received either abiraterone or enzalutamide, however, maybe used either before or after docetaxel, as this was allowed in either situation within the context of the PROfound trial.

And so the panel is recommending olaparib as an option for men with mCRPC, previous enzalutamide or abiraterone exposure, and homologous recombination repair. In the second line, after first-line abiraterone or enzalutamide, independent of docetaxel therapies, a category 1 recommendation, as second-line treatment after docetaxel is a category 2B, and as a subsequent line of therapy is a category 1 recommendation. Notably, the panelists listed here the 14 gene mutations in which olaparib may be indicated and while PPP2R2A was included as a mutation in PROfound, the benefit of olaparib was not observed in this patient cohort and so it is not recommended and not FDA approved.

TRITON2 provides the data that we use for the approval of rucaparib and this is a phase two single-arm study. And notably in this study, patients had to receive one novel hormonal agent as well as one prior taxane. The primary endpoint of overall response rate demonstrated a response of nearly 44% in BRCA1/2 patients with a radiographic progression-free survival with a median of nine months.

And so on the basis of these data, rucaparib received accelerated FDA approval as of May 2020. And unlike the olaparib approval, patients here had to have a previous line of chemotherapy in addition to prior treatment with enzalutamide or abiraterone. Additionally, the approval is limited to those with mutations in BRCA1 or BRCA/2. Finally, the full FDA approval is contingent on the results of the phase three TRITON study, which was a randomized trial of rucaparib versus abiraterone, enzalutamide, or docetaxel in patients who had previously received a novel hormonal agent, but not chemotherapy.

So in terms of panel recommendations, rucaparib is an option for men with mCRPC and BRCA/1 or BRCA/2 mutations following a first-line abiraterone or enzalutamide, or after additional docetaxel or as a subsequent line of therapy, a third line, or on. When patients are not fit for chemotherapy, rucaparib may be considered even if taxane-based therapy has not been given. And notably, the panel specifies that somatic analysis of BRCA/1 or BRCA/2 using a circulating tumor DNA sample is the preferred method of identifying patients with these mutations.

So here we are highlighting treatment options from the NCCN guidelines with an emphasis on those that we presented in this talk. Sipuleucel-T may be considered for patients who have received no therapy for mCRPC. For those who have received prior hormonal therapy, sipuleucel-T, olaparib, rucaparib or docetaxel may be considered. For those who received docetaxel, but not prior hormonal therapies, again, in the context of this talk, pembrolizumab and sipuleucel-T may be considered, although are not preferred regimes. And those who have received both docetaxel and novel hormonal therapies, olaparib, pembrolizumab, and rucaparib may have a role.

And so I'd like to take the time to thank you for joining us for this discussion of the NCCN guidelines, focusing on novel treatment approaches in mCRPC, and hope that you will join us for further talks about other aspects of these guidelines. Thanks again.