Like most other cancers, mCRPC is a heterogeneous disease, and optimal approaches for the entire population may not be best for each individual patient. Prostate-specific membrane antigen (PSMA)–targeted radioligand therapy works well in some subsets of patients, but not in all. PSMA avidity as measured by a standardized uptake value cutoff might be used to predict benefit from PSMA-targeted therapies as opposed to chemotherapy. In abstract 10 from the 2022 Genitourinary Cancers Symposium, Buteau et al tested the reasonable notion that a high PSMA–expressing tumor will respond to PSMA-targeted therapy. They should be credited for conducting that analysis and for resisting the temptation to accept that assumption without critically testing it.

The biologic heterogeneity that is demonstrated by patient-specific vulnerabilities to immunotherapy, radioligand therapy, or a combination of both is poorly understood. Several lines of inquiry are being explored to understand the mechanisms behind the observed therapeutically relevant heterogeneity. These investigations point to the following 3 groupings: (1) targeting the complex network of molecular pathways and applying that knowledge to develop molecularly targeted therapies; (2) exploiting the understanding of the role of the tumor-associated microenvironment that accounts for the nonrandom distribution of metastases with the predominance of osseous metastases and life-prolonging effects of targeting bone; and (3) leveraging the identification of cancer-associated transmembrane molecules to selectively direct therapeutic agents to malignant cells (eg, radioligand and bispecific antibodies) targeting surface antigens, including those antigens that are implicated in cancer pathways. 

Our understanding of the molecular complexities of prostate cancer has been used to prioritize targetable driver pathways. This is best illustrated by targeting DNA damage repair deficiencies with poly (ADP-ribose) polymerase inhibition, with the predicted subset of patients benefiting. Research from the past decade has identified targetable pathways that are implicated in the transition from androgen dependence to resistance to androgen signaling inhibition. The clinical impact from targeting these pathways has not been as striking as that observed with targeted therapy in other cancers such as lung or breast cancer, where the concept of oncogene addiction seems to be more important. The advances in prostate cancer from targeted therapy have been largely incremental, with modest impact.

A second group of treatments has been developed in recent years, including those that exploit the tumor-associated microenvironment and the characteristic that bone metastases are the principal site of therapeutically resistant prostate cancer progression. The life-prolonging effects of radium-223 suggest that the further development of bone-specific therapies can lead to greater improvements in outcomes. The efficacy of targeting the tumor-associated bone microenvironment is analogous to the reported life-extending effects of the resection of hepatic metastases in colon cancer or pulmonary nodule resection in select sarcomas. 

An appreciation of the merits of targeting unique properties of the surface of cancer cells has led to the emergence of cell surface–targeting therapies as a promising treatment strategy across cancer types. This pan-cancer evolution of therapy from targeting molecules in pathways to targeting unique cancer cell surface features has proven to be effective in prostate cancer. The identification of novel targets, added to the established efficacy of targeting PSMA, is encouraging, and these novel targets include STEAP1 and KLK4. The elucidation of the upstream and downstream pathways that drive the expression and function of candidate cell surface targets can be exploited to develop rationally designed combinations of molecularly targeted therapies and cell surface–targeting agents. This may lead to the development of more effective therapeutic strategies. 

In a general session at this year's symposium, Tanya B. Dorff, MD, reviewed promising targets in this niche. The approaches exploit the exposure of cell surface antigens, so we can investigate alternative antigens such as DLL3, KLK2, and PSMA as a way of delivering drugs, toxins, and radioligands to the tumor. Understanding the distribution of cell surface “candidate targets”* on the individual cell surface, and across cells within an individual with cancer, will inform the development of combinations incorporating such therapies. To achieve this aspirational goal, we will need to account for the heterogeneity of expression across the whole population of cancer cells, including whether the targets are co-expressed by a cancer cell or 1 target is exclusively expressed in a cancer cell. We will also need to account for heterogeneity across the population of cancer cells in their vulnerabilities to specific toxins.

Intriguing findings reported at the symposium suggest that dipeptidyl peptidase (DPP) inhibition may be efficacious. This is based on the principle that BXCL701, a DPP inhibitor (primarily DPP 8/9 and DPP 4), may be able to trigger the inflammasome and favorably alter the immune microenvironment. Interestingly, BXCL701 is a well-tolerated drug and appears to be able to alter the consequences of the adaptive immune response. Zhang and colleagues reported that giving the PD-1 inhibitor pembrolizumab in combination with BXCL701 had encouraging activity in patients with advanced refractory mCRPC of adenocarcinoma phenotype (abstract 125). 

It will be critical to efficiently build on the “embarrassment of riches” in prostate cancer treatment through well-designed clinical trials of candidate treatment strategies that are organized in planned periods. We will also need to build on the emerging molecular classification of prostate cancer and the methodologies of characterizing patients clinically. These efforts will involve the collection and analysis of complex data sets that will lead to new therapeutically relevant insights. 

*Addendum: On March 23, 2022, subsequent to this interview, the US Food and Drug Administration (FDA) approved lutetium Lu 177 vipivotide tetraxetan (formerly referred to as ¹⁷⁷Lu-PSMA-617) for the treatment of progressive PSMA-positive mCRPC. The FDA also approved a complementary gallium-68–based agent indicated for positron emission tomography of PSMA-positive lesions.