Aggressive-Variant Prostate Cancer (AVPC) - a success story’s Dark Side
Prostate cancer is one of the oldest success stories in medical oncology. From the discovery of its androgen dependence to the newest iteration of novel androgen receptor signalling inhibitors (ARSIs) , our understanding and management of prostate adenocarcinoma has been improving in fits and spurts for over a century. Nowadays, widespread use of ARSIs like darolutamide or enzalutamide, novel treatments such as Lu-PSMA and improved imaging modalities such as PSMA-PET scans have improved the outcomes for patients with prostate cancer immeasurably.
However, every story has a dark side.
With improved treatment of androgen-dependent prostate cancer, a new threat has emerged. Aggressive-variant prostate cancer (AVPC) is a rare but increasingly-common clinical entity that is characterised by androgen-independent growth, bulky or high-volume disease without elevated serum prostate-specific antigen (PSA) levels, and rapid progression with poor prognosis. It is an almost invariably fatal disease, and treatment options are scant. Fortunately, emerging strategies to combat this newly-identified variant of prostate cancer.
But what is AVPC? In a review article published in Cancers in 2020, Nicholas Spetsieris and colleagues from the MD Anderson Cancer Centre at the University of Texas examine this question in significant detail.
Firstly, it is important to note that AVPC is an umbrella term for prostate cancers that behave unusually aggressively. These cancers most commonly demonstrate some neuroendocrine (NE) differentiation, but this is not always the case. In 2013, the following criteria was set out to define AVPC. Meeting one of these criteria confirms a diagnosis of AVPC:
Histological evidence of pure or mixed small cell prostate cancer (SCPC)
Presence of only visceral metastases
Predominantly lytic bone lesions
Bulky (≥5cm) lymphadenopathy or large (≥5cm) high-grade (Gleason ≥8) tumour mass in prostate or pelvis
Low PSA with extensive bone metastatic disease
Presence of NE markers on histology (Chromogrannin A and synaptophysin) or serum (CgA and gastrin-releasing peptide) combined with either elevated lactate dehydrogenase (LDH), malignant hypercalcaemia or elevated carcinoembryonic antigen (CEA)
Progression of prostate cancer in less than six months after onset of hormone therapy
AVPC is a rare but increasingly common phenomenon, both due to improvements in treatment of standard prostate cancer, and an increased awareness of its presentation. De novo AVPC/neuroendocrine prostate cancer (NEPC) remains exceptionally rare (<2%), but differentiation in the setting of previous androgen deprivation (ADT) has been reported in up to 20% of cases in some series. The current hypothesis is that this “treatment-emergent” AVPC is caused by clonal evolution of previously standard prostate adenocarcinoma, where constant stress of androgen-dependent cells drives cancer towards an androgen-independent state. However, other hypotheses exist, including the loss of tumour-suppression genes such as TP53 and phosphatase and tensin homolog (PTEN) and the acquisition of transcription factors (SOX2,11).
Regardless of the mechanism, the result is a devastating and rapidly progressive cancer.
Characteristics of AVPC. Image courtesy of Cancer (2020)
Now that we know what AVPC is, we must look at how to assess and treat it.
As mentioned above, many of the criteria for AVPC can be diagnosed through a combination of clinical and radiological assessment. In a patient with rapidly progressive, bulky disease without significant response to anti-androgen therapy or significantly elevated PSA, AVPC should be considered. NE-specific serum markers such as chromogranin A (CgA) and neuron-specific enolase (NSE) have been reported to correspond with disease progression and response. Some studies have also suggested that FDG or DOTATATE-PET scans may be used to assess aggressive disease that no longer expresses prostate-specific markers such as PSMA. However, a biopsy may be useful in confirming this diagnosis as well as searching for targetable mutations, such as deficiencies in homologous repair (HRD) and mismatch-repair (MMR) proteins.
Data on the standard treatment of AVPC is limited, and much of it is extrapolated from the treatment of small-cell lung cancer. Combination of a platinum agent with etoposide has been evaluated in multiple phase II studies of AVPC, largely with poor results. In addition, the dose of carboplatin (AUC 4 vs AUC 5) and etoposide (80mg/m2 vs 100mg/m2) was not consistent across the studies. Nevertheless, this option remains a commonly-used regimen for patients with AVPC, particularly if small-cell or large-cell histology is confirmed.
Image courtesy of Cancer (2020)
Other studies have examined the combination of a platinum with a taxane agent. For example, Aparicio et al. examined combining carboplatin and docetaxel, followed by salvage cisplatin and etoposide. As per the table above, 47% of patients had a PSA response, but only 34% of patients had an objective response per RECIST. Finally, Corn et al. examined combining carboplatin and cabazitaxel, an agent currently used as standard treatment for heavily-pretreated prostate cancer. Enrolling patients with both standard PC and AVPC, the combination of carboplatin and cabazitaxel numerically outperformed cabazitaxel alone in terms of PSA response, objective response and PFS. Unfortunately there was no benefit in overall survival in the intention-to-treat (ITT) population. A post-hoc analysis did demonstrate a benefit with the combination in patients who met criteria for AVPC, but the significant of this is uncertain.
It is clear that new strategies are required for the treatment of AVPC. Fortunately, there are potential new directions currently under investigation.
Several phase I/II studies are examining the combination of immunotherapy with CTLA-4 and PD-(L)1 blockade in rare cancers, including AVPC. As perhaps one would expect, the initial results have been a mixed bag: a small trial of avelumab that was terminated early due to poor recruitment in the setting of the COVID-19 pandemic demonstrated poor efficacy, with an overall response rate of 6.7% and a median OS of 7.4 months. The novel agent tabalostat (an inhibitor of dipeptydl peptidase) in combination with pembrolizumab, by contrast, demonstrated promising efficacy, with a median OS of 13.6 months, and a 12-month overall survival rate of 56.5%.
Other options include the use of PARP inhibitors to target potential deficiencies in DNA repair. One phase II study examined the use of olaparib as maintenance therapy after a combination of carboplatin and cabazitaxel. The median PFS was 4.9 months in patients with olaparib and 2.3 months in patients with observation alone, though there was no benefit in overall survival. It is worth noting that in this study 37.5% of patients who commenced chemotherapy progressed prior to randomisation, demonstrating the difficulty of conducting large-scale trials on patients with AVPC.
Finally, myriad novel targets are currently under investigation. One example is deltalike ligand 3 (DLL3), a peptide frequently expressed in neuroendocrine carcinomas. A phase I/II study of rovalpizutumab enrolled 21 patients with NEPC (out of 101 patients with NEC of any origin). ORR was 14% amongst the NEC cohort, and response appeared to favour tumours with high DLL3 expression.
The Bottom Line
AVPC is a rare but clinically important prostate cancer variant associated with poor prognosis, rapid progression and significant morbidity and mortality. Current standard of care treatment is centred around combination chemotherapy with a platinum agent, but newer targets are under investigation.
Sources.
Spetsieris, N., Boukovala, M., Patsakis, G., Alafis, I., & Efstathiou, E. (2020). Neuroendocrine and Aggressive-Variant Prostate Cancer. Cancers, 12(12). https://doi.org/10.3390/cancers12123792
Rahul Raj Aggarwal et al., First-in-class oral innate immune activator BXCL701 combined with pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC) of small cell neuroendocrine (SCNC) phenotype: Phase 2a final results. JCO 41, 176-176(2023). DOI:10.1200/JCO.2023.41.6_suppl.176
Aaron Scott Mansfield et al., A phase I/II study of rovalpituzumab tesirine in delta-like 3-expressing, advanced solid tumors. JCO 38, 3552-3552(2020). DOI:10.1200/JCO.2020.38.15_suppl.3552
Patrick Glen Pilié et al., Randomized phase II study of olaparib (Ola) maintenance following cabazitaxel-carboplatin induction chemotherapy (CabCarb) in men with aggressive variant prostate cancer (AVPC).. JCO 41, 196-196(2023). DOI:10.1200/JCO.2023.41.6_suppl.196
Brown, L. C., Halabi, S., Somarelli, J. A., Humeniuk, M., Wu, Y., Oyekunle, T., Howard, L., Huang, J., Anand, M., Davies, C., Patel, P., Staats, J., Weinhold, K. J., Harrison, M. R., Zhang, T., George, D. J., & Armstrong, A. J. (2022). A phase 2 trial of avelumab in men with aggressive-variant or neuroendocrine prostate cancer. Prostate Cancer and Prostatic Diseases, 25(4), 762-769. https://doi.org/10.1038/s41391-022-00524-7
