2020 Hindsight and 2021 Foresight

By all accounts outside of our world of prostate cancer, 2020 was a pretty bad year. That much has been decided and agreed upon by just about everyone in the world. With that said, 2020 was not a horrible year in the progress against prostate cancer. Several new developments arose and progressed in the past year that can give us hope and new options for patients. Along those lines, it can give us an optimistic look at 2021 as well, as the developments of 2020 are but a precursor to some of the moments that may await us in 2021.

First, the highlights of 2020 (As I see them)

PARP inhibitors

It feels like poly (ADP-ribose) polymerase (PARP) inhibitors have been in circulation in prostate cancer for a long time, but the data became real in the typical clinic this year. Large Phase III studies have been underway for a while and the TOPARP B study was published in the New England Journal several years ago, but the reality is it wasn’t until this past year, 2020, that regulatory approval was granted for PARP inhibitors in prostate cancer. Further, data suggest that not only do these therapies induce responses, but treatment with them in the context of BRCA1 or, more commonly BRCA2, results in an overall survival advantage. The results from the PROfound study, detailed elsewhere in my blogs and on Urotoday.com, open up this possibility of treatment for patients with mCRPC and one prior AR targeted therapy who harbor a host of mutations including BRCA1, BRCA2, and a long list of mutations that occur in frequencies of 1-2% of metastatic castration-resistant prostate cancer (mCRPC) patients. Although rare, these mutations are out there, and the approval of them now demands of us that we perform next-generation sequencing on patient tumors, even if germline results are unrevealing.

The trial design that approved a PARP inhibitor

To date, every novel therapy in mCRPC that has received FDA approval in the United States did so based on a randomized controlled trial in which a comparator arm received a placebo or an existing standard of care therapeutic. In all cases, the studies had to enroll 500-1200 patients, randomly select the treatment and observe a ‘rate of events’ such as deaths or progression of disease. The TRITON 2 study broke that trend by resulting in the approval of rucaparib, a PARP inhibitor, for prostate cancer, based on tumor response in a Phase II (yes, a Phase II) study.

Now, there are several caveats that deserve attention. The first is that this is not a full approval and there is a Phase III study, TRITON 3, that is continuing to develop. The second is that this is a targeted therapy that requires a positive biomarker – which is a good thing! Because unlike all the randomized trials mentioned, selection for rucaparib treatment was based on the need for a BRCA1 or BRCA2 alteration, not solely on progressive disease in a clinical state, but the approval does require prior taxane therapy. The final caveat is that "response" in a prostate cancer patient requires measurable disease, and a majority of patients in the post-taxane space do not have measurable disease. Will this become a model for future drug approvals? It's too early to say, but nonetheless the door is cracked open to future accelerated approvals.

Treatment of nmCRPC with novel AR targeted drugs improves overall survival

Results of the PROSPER and SPARTAN studies showed us previously that treatment with an AR targeted drug can delay metastasis by a significant degree in patients with nonmetastatic CRPC (nmCRPC), but questions remained about whether that was sufficient enough to prescribe these drugs in that setting given their high cost and potential safety concerns. 2020 brought us survival data from these two trials as well as from the ARAMIS trial, definitively demonstrating that earlier anti-tumor therapy is better. If it wasn’t already there, the results of ARAMIS, PROSPER, and SPARTAN should put the final nail in the coffin on the notion that we should 'watch and wait' in CRPC until the patient develops symptoms. Doing so now in the face of so many active therapies would be bad medicine.

Targeted therapy for PTEN loss

The IPATential150 study with ipatastertib, an AKT inhibitor, represents the first real success after decades of trying to target the PTEN/AKT/PI3Kinase pathway. The study, which randomized 1100 patients with mCRPC to receive abiraterone plus ipatasertib to abiraterone with a placebo with the major entry criteria being that the patient's tumor must demonstrate loss of PTEN. This is a bit tricky because the loss of PTEN could be determined genomically, without an understanding of what is going on with the protein, or could be determined by directly measuring the PTEN protein through immunohistochemistry. Indeed, the best results were identified in those patients who have PTEN loss on immunohistochemistry (IHC) who received ipatasertib.

PSMA targeted imaging takes a big step forward

There were two big advances in 2020 with respect to PSMA imaging. The first was late in the year with the approval of Ga68-PSMA PET scans at two locations in the United States – UCSF and UCLA. Next, we will have to watch for the roll-out of this technology to other centers and clinics. The main limiter at individual sites involves the development of the 68Ga tracer used in the imaging. The indication thus far is for pre-treatment staging or in the setting of serologic relapse after surgery or radiation.

The other development in this area was the CONDOR study that demonstrated that PSMA targeted 18F-DCPyL. In this study, 18F-DCPyL imaging was paired with standard imaging, and clinicians were asked to rate how the novel images guided their management in patients with a rising prostate-specific antigen (PSA) following definitive local therapy. Almost two-thirds of patients evaluable after this imaging underwent a change in their management based on the findings – 79% resulting from a positive scan (e.g. changing from a plan of salvage local therapy to doing systemic therapy) and 21% resulting from a negative scan (e.g. changing from systemic therapy to a salvage local therapy).

Looking forward: What to expect in 2021

Trying to predict when a clinical trial will read out exactly is a tough task. Most clinical trials are designed to identify a modification in the risk of a certain outcome ( such as disease progression or death) comparing an existing therapy to a novel one. In many cases, the predicted time of conclusion of a therapy is missed, perhaps due to slower than expected accrual, or a control arm that has a better than expected outcome. Thus, it is hard for me to state when certain big trials such as VISION (with PSMA lutetium-617 compared to standard of care) or other Phase III studies will readout.

I can state, however, what I will be watching with some interest.

  • More data on cellular therapies. Treatments like CART’s and BiTes and other approaches are coming. The data on the AMG 160 BiTE was interesting this year and suggests that if we can get T cells closer to prostate cancer tumors, we may be able to induce responses. This agent is going to move into Phase III. Also, CART studies in prostate cancer may begin to tell a story about whether this approach.
  • More data on therapeutic radioligands. Lutetium targeting is emerging as a potentially big change in the clinic and appears to possibly be favorable to chemotherapy in the third-line setting. But, lutetium is not the only radioligand out there. Alpha emitters tagged to PSMA tracers like actinium and bismuth are in the clinical setting and may lead to novel approaches. Watch this space.
  • More on PARP inhibitors outside of the DNA-repair gene defect (DRD) setting. There is reason to be encouraged about the potential for PARP inhibitors to serve as adjuncts to a variety of approaches including AR targeted therapies, checkpoint inhibitors, and radiation approaches. Trials are underway and the data from the UK on the combination of abiraterone plus olaparib a few years ago suggested that such approaches may be viable.
  • Greater appreciation for complex genomics – we have now gotten to the point where many if not most clinicians who treat prostate cancer are growing comfortable ordering and evaluating genomic tests. Understanding the differences and some of the nuances of somatic versus germline testing is now standardized. As we move forward, we will hear more of our colleagues discussing cases based on PTEN, RB1, and TP53 status, among others. Genomic testing will go from a binary “actionable mutation or not” to a more nuanced understanding of these high-risk gene alterations. An even bolder prediction? Genomic descriptors may topple the Gleason score in the language of ascribing pathological information to the outcome.

Written by: Charles Ryan, MD, B.J. Kennedy Chair in Clinical Medical Oncology, Professor of Medicine and Director of the Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota

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