Traditionally, we have lacked success with combinations in advanced prostate cancer, especially with docetaxel (ie, nothing seemed to combine well with it). However, with the novel androgen receptor (AR)–targeted agents, some newer combinations seem to be promising, especially those that add a different mechanism of action, such as a poly (ADP-ribose) polymerase (PARP) inhibitor. In contrast, we see that combining 2 novel AR-targeted agents does not appear to be beneficial.

PARP inhibitors seem to synergize well with AR-targeted agents. We know that proteins in the PARP family, such as PARP-1, have been implicated in the regulation of gene expression in prostate cancer, in addition to their role in DNA repair. Mechanistically, PARP-1 is recruited to sites of AR function, where it promotes AR occupancy and function. So, it makes sense that these drugs could work well together.

It is also interesting to combine PARP inhibition with radiotherapies because you are inducing DNA damage and then blocking DNA repair in cancer cells. We have seen some unfavorable effects with novel hormonal therapies plus radium-223 (ie, more fractures with the combination than with radium-223 monotherapy), but it remains to be seen whether lutetium Lu 177 vipivotide tetraxetan, which was recently US Food and Drug Administration approved, may combine better with AR-targeted agents.

We are just on the brink of testing some of these combinations. With the tumor heterogeneity in prostate cancer, it is very appealing to use agents with different mechanisms of action to gain a more complete response. Teasing out the right molecular population can be difficult in CRPC. The earlier use of AR and PARP inhibitor combinations, before we have castration resistance, could be very interesting, and there are some ongoing trials that are looking into that.

To date, we have at least 6 novel mechanisms of action from which patients with mCRPC can benefit, all of which have level-1 evidence showing an improvement in overall survival. We have the AR-targeted drugs, which include abiraterone, enzalutamide, apalutamide, and darolutamide. We have the taxanes (ie, docetaxel and cabazitaxel), which are microtubule inhibitors and work through a mechanism that is very different from that of the AR pathway–targeted therapies. We have radium-223, a radiopharmaceutical that, as Dr Dorff alluded to, creates double-stranded DNA breaks, promoting apoptotic effects in prostate cancer cells. PARP inhibitors, which represent a fourth novel mechanism of action, leverage synthetic lethality in the context of homologous recombination repair deficiency. We also have immunotherapy in the form of sipuleucel-T, which works by enhancing the presentation and recognition of prostate cancer antigens, and in pembrolizumab, which has a tumor-agnostic indication for patients with high microsatellite instability or even tumor mutational burden elevation. Now we have a sixth novel mechanism of action in the form of prostate-specific membrane antigen (PSMA)–targeted radioligand therapy, where lutetium is conjugated to a small molecule that binds PSMA.

Once patients develop mCRPC, they are already receiving some form of combination therapy (ie, typically primary androgen deprivation therapy [ADT] plus 1 of these 6 novel mechanisms of action). What is particularly exciting to me is determining how we can further use combination strategies, such as primary ADT plus an AR inhibitor plus a taxane, or ADT plus an AR inhibitor plus a PARP inhibitor, or ADT plus a PARP inhibitor plus radiotherapy with radium-223 or PSMA-targeted radioligand therapy. It will also be important to determine whether we can use immunotherapies in conjunction with chemotherapies, in conjunction with a PARP inhibitor, or in conjunction with an AR-targeted drug. 

As we move from left to right in the disease continuum, from hormone-sensitive to castration-resistant disease, it can become challenging to define optimal therapy in terms of adding different mechanisms. In the metastatic hormone-sensitive setting, we move the needle dramatically when we start intensifying ADT, as demonstrated from data ranging from earlier studies such as CHAARTED and LATITUDE to more recent studies such as PEACE-1 and ARASENS. 

However, in patients with mCRPC, who are more heavily pretreated, the heterogeneity of the disease can make things much more challenging. For many patients with CRPC, the disease is not hormone insensitive; however, resistance mechanisms that develop may not be well characterized, such that we lack a means to overcome them therapeutically. Additionally, there is the potential for treatment-emergent neuroendocrine prostate cancer. While there may be a temptation to use drug combinations more liberally in mCRPC, we really have to be sure that the benefit justifies the additive toxicity. 

I think that the data from the PROpel and the MAGNITUDE trials, with PARP inhibition in selected and unselected populations, remind us that research is not easy and is not always straightforward; many of us are waiting for more data, and I think that the jury is still out on PARP/AR inhibitor combinations in non–DDR-mutated patients. Do I believe that we will eventually develop rational combinatorial strategies? Absolutely. But I think that, right now, the best data for combination therapy and treatment intensification are in the metastatic castration-sensitive disease setting.