Eric J. Small: Thank you for the opportunity to discuss this important topic. These are my disclosures. Primary small cell prostate cancer is very rare, accounting for 1% of newly diagnosed prostate cancers. It frequently presents with widely metastatic disease and classically has been described as an AR-null phenotype and a non-PSA-producing cancer. Visceral metastases are common. This cancer is generally not responsive to AR-targeted therapy and presents with explosive, virulent disease with a very shortened survival. Importantly, a treatment-associated small cell neuroendocrine prostate cancer, which we will term t-SCNC, has emerged as a resistance phenotype in mCRPC and it is highly reminiscent of primary small cell cancer.

Nearly a decade ago now, Dr. Aparicio and colleagues coined the phrase “aggressive variant prostate cancer” referencing a phenotypic syndrome that included seven different adverse risk categories, which are shown here, including the small cell histology that I've alluded to. After treating approximately 100 patients with AVPC with a specific regimen, Dr. Aparicio and colleagues evaluated the impact of each criterion on PFS and OS. I've placed green dots identifying those variables that when present, resulted in impaired outcomes, in red, those that did not. These investigators then went on to look for common genomic findings and found that 48% of AVPC, compared with 39% of unselected CRPC, had loss of function findings in two of three genes, RB, p53, and PTEN. What I'd like to do now is to focus on the histologic subset, which is very similar to the treatment-associated small cell neuroendocrine prostate cancer that we found.

As part of the Stand Up to Cancer, Prostate Cancer Foundation West Coast Dream Team, we've undertaken metastases, of biopsies of metastases in CRPC patients. The table here demonstrates the sites of the biopsies. In the first 295 biopsies that were positive, we identified treatment-associated small cell neuroendocrine prostate cancer, either alone or coexistent with adenocarcinoma, in a surprisingly large percentage of patients, 17%. Rahul Aggarwal has reported on the clinical and genomic characterization of these patients. It's important to understand that t-SCNC evolves from adenocarcinoma, with AR signaling associated gene expression, shown here, falling but only in those progression biopsies that showed small cell neuroendocrine prostate cancer. In other words, when patients progressed and the adenocarcinoma remained adenocarcinoma, these changes were not observed.

We'll come back to the issue of AR expression in these patients. So, let's look at the clinical features of SCNC. It carries a very poor prognosis. In the genomic cluster, 17.7 months overall survival compared with 4.2 months overall survival in adenocarcinoma CRPC. The presence of visceral metastases was not synonymous with SCNC, and visceral metastases were found nearly as frequently in adenocarcinoma. In fact, the metastasis biopsy site did not predict SCNC, with the majority of liver biopsies in fact not showing t-SCNC and showing adenocarcinoma. Unlike primary small cell, PSA levels in these patients can be quite elevated as shown here. However, some SCNC patients do have very low PSA levels. Unlike primary small cell, PSA is almost never completely absent but can be quite low.

We looked at a subset of patients that were low PSA-secreting. While t-SCNC was three times more common in this group of patients, it only comprised one-third of patients. And they all had worse survival, more likely to have visceral metastases, more RB1 and p53 mutations, and did not respond as well to androgen signaling inhibitors, and appeared to feel better with taxane-based chemotherapy. Unlike primary small cell, AR staining shown in the right panel is commonly seen in SCNC. Further, genomic AR amplifications are just as common in SCNC as it is in adenocarcinoma, 67% versus 51%. Nevertheless, despite AR amplification, AR transcriptional activity is in fact repressed, perhaps accounting for some of those patients with low PSA levels.

While small cell prostate cancer is often thought of as emerging from high Gleason score patients, that was not the case in this series as shown here. We also uniformly measured neuron-specific enolase and chromogranin A and observed that serum neuroendocrine markers, while slightly more elevated, had very low specificity for SCNC and a negative predictive value of 98%, of 95%, excuse me. And thus, these markers are useful as a rule-out test. Finally, the mutational profile on t-SCNC shared some but not all features with AVPC. We found enrichment of loss of function variants in TP53 and/or RB1 in 83% of SCNC, while PTEN seemed less ubiquitous. Furthermore, in 100 samples in which we undertook whole genome sequencing, we found that of all genomic combinations, a two-hit RB1 loss resulted in the worst survival shown here.

So, let's look then at the overlap of these two groups of patients, SCNC and AVPC. SCNC, I think is a subset of AVPC and it imparts a particularly poor prognosis. However, as I've shown you, it cannot be identified by clinical features so we strongly recommend biopsy of accessible metastases in men with progressive prostate CRPC. The presence of visceral metastases is by no means diagnostic of SCNC. And conversely, the absence of visceral mets does not rule out SCNC. As we've discussed, high PSA levels do not rule out SCNC and neither does robust AR expression. Conversely, low PSA-secreting patients do poorly. However, they only harbor SCNC in about one-third. Serum neuroendocrine markers lack specificity for histologically defined SCNC. And whenever possible, p53, RB1, and PTEN status should indeed be checked. In our hands, deep RB deletions and loss are of particular concern.

Given the high frequency and poor outcome with these tumors, what are the therapeutic implications? How do we approach them? NCCN guidelines reflect the lack of options for these patients. This slide summarizes what is essentially in the NCCN guidelines and summarizes many of the platinum-based combinations reported with a reasonable but short-lived response proportion. The only randomized trial was undertaken by Dr. Aparicio's group, comparing Carbo Cabazi to Cabazi alone. It should be pointed out that in 70% of patients, this was given as frontline chemo and that although the study was enriched for, it was not restricted to AVPC, with slightly over half of the patients being comprised of AVPC. Nevertheless, there was a modest improvement in PFS but not overall survival.

In small cell lung cancer, adding a checkpoint inhibitor to chemo and in particular, atezolizumab or durvalumab, had statistically significant impact and improvement in overall survival as shown here, and led to approval. Whether this has an impact in prostate SCNC is neither known nor approved but by extrapolation has been used by some. Lastly, also not approved, I encourage you to keep your eyes on the development of treatment with therapies targeting differentially expressed targets. DLL3 and its role in small cell neuroendocrine cancer has been elegantly explored and described by Dr. Beltran, and immune targeting trials are underway. Dr. Aggarwal is leading a study of CD46 antibody drug conjugate, to name just two examples.

The therapeutic approaches to consider in AVPC and SCNC patients are summarized here. We believe that a biopsy when possible should be undertaken. Neither the site of the disease or PSA level is diagnostic and this is an important piece of information to begin. AR expression is retained but transcriptional activity is lower, perhaps responsible for the muted, but not absent, response to ASIs. And furthermore, potentially as a therapeutic approach, co-targeting or restoring dependence on AR is being explored. Certainly, RB, p53, and PTEN status should be established. In our hands, RB in particular, carries poor prognosis in the small cell neuroendocrine cancer and could be the basis for choosing chemotherapy.

Importantly, periodic imaging is recommended to assess response to treatment, particularly if the PSA is low since progression can occur while PSA remains low. Platinum-based chemotherapy is certainly warranted. Cabazi/Carbo platinum appears to have a modest advantage over Cabazitaxel, but we really don't know if this should follow Taxotere, if Taxotere should be combined with platinum. It's also unclear if adding a checkpoint inhibitor to chemotherapy is of benefit, but by extrapolation, it appears that it may be. And whenever possible, needless to say, clinical trials should be considered. So, I'd like to acknowledge the many, many contributors to the West Coast Prostate Cancer Dream Team that provided much of this data, in particular Rahul Aggarwal, Felix Feng, and Jiaoti Huang really helped delineate this entity. And with that, and this wonderful picture of our last meeting for the APCCC, I'd like to thank you for your attention. Thank you very much.