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Therapeutic options for advanced prostate cancer are rapidly evolving, making it challenging for clinicians to apply clinical trials results to daily practice, noted Nataliya Mar, MD, of the University of California Irvine, and colleagues, writing in a review in .

The review covers a range of topics designed to help oncologists make clinical decisions, including how molecular biomarkers predictive of response or resistance to therapy can guide treatment, as well as the optimal timing of therapy in patients with biochemical recurrence, treatment approaches in low-volume versus high-volume metastatic castrate-sensitive prostate cancer (mCRPC), and the types of agents available beyond androgen-deprivation therapy (ADT).

"Additionally, familiarity with emerging treatment strategies is important," the authors wrote, noting that the aim of the review was to address the "gray areas and challenging questions in advanced prostate cancer management that frequently arise in clinical practice."

In the following interview, Mar discusses some of these clinical questions and emerging strategies.

One promising predictive biomarker of treatment resistance you mention is AR-V7. What can you tell us about that?

Mar: AR-V7 is a splice variant of the androgen receptor, which causes it to be constitutively active. In men with metastatic castrate-resistant prostate cancer, AR-V7 positivity in tumor cells has been associated with primary or acquired resistance to second-generation anti-androgen therapies such as abiraterone or enzalutamide.

Meanwhile, AR-V7 status does not appear to correlate with responses to taxane-based chemotherapy in this patient population.

The PROPHECY trial collected AR-V7 data at various time points using three different assays in men with mCRPC treated with investigator's choice of abiraterone or enzalutamide followed by taxane-chemotherapy upon disease progression.

Although not all study results have been reported, patients who were AR-V7 positive demonstrated inferior radiographic progression-free survival and overall survival to abiraterone/enzalutamide compared to those who were AR-V7 negative.

This study also demonstrated that AR-V7 positivity can become detectable upon disease progression in men treated with abiraterone/enzalutamide who were AR-V7 negative at baseline, suggesting an important mechanism of resistance.

There is also some early data suggesting that positive to negative AR-V7 conversion is possible following taxane-based chemotherapy. As such, it is a promising predictive biomarker that can potentially influence clinical treatment decisions between these two therapies. There are several different assays that can assess for presence of AR-V7 in circulating tumor cells, although none are routinely used in the clinical setting at this time.

Localized prostate therapy in low-volume mCRPC is being investigated. What has been found so far?

Mar: Several published trials have suggested that addition of definitive radiation therapy to the prostate improves outcomes in low-volume mCRPC. In a subgroup analysis of patients with less than five bony metastasis within the HORRAD trial, there was a 32% risk of death reduction with addition of radiation to ADT.

Addition of prostate radiation therapy to standard-of-care treatment (ADT +/- docetaxel chemotherapy) improved 3-year overall survival (81% vs 73%, HR 0.68) in the newly diagnosed low-volume patient subset within the STAMPEDE trial.

These were practice-changing results and have since been incorporated into the NCCN [National Comprehensive Cancer Network] guidelines. The ongoing multi-arm PEACE 1 phase III trial examines addition of radiation to standard-of-care therapy in the era of second-generation androgens (i.e., abiraterone). Other ongoing studies including TROMBONE and g-RAMPP are exploring whether there is a role for radical prostatectomy in this patient subset.

Another concept being explored is whether androgen receptors can be resensitized via testosterone manipulation. How does this work?

Mar: A very interesting concept is whether the androgen receptor in the castrate-resistant setting can be resensitized simply with testosterone manipulation, the so-called bipolar androgen therapy (BAT). This refers to patients treated with ADT and receiving monthly testosterone injections, which lead to a transient supraphysiologic rise of serum testosterone to more than 1,500 ng/dL and a subsequent decrease to castrate testosterone levels of less than 50 ng/dL.

These wide testosterone fluctuations can cause upregulation of androgen receptor axis signaling.

The TRANSFORMER trial examined patients with mCRPC who progressed on abiraterone and were randomized to receive BAT versus enzalutamide, with crossover to the alternative arm allowed post-clinical or radiographic progression.

Patients who underwent BAT and then received enzalutamide had improved time to prostate-specific antigen (PSA) progression, higher rates of 50% decline in PSA, higher objective overall response rates, and longer time from therapy initiation to progression on crossover. However, these results are not yet ready to be used in clinical practice due to the small study small sample size, and larger trials are warranted.

Finally, one radioisotope you mention being developed to link with prostate-specific membrane antigen is Lu-PSMA-617. Can you tell us about this?

Mar: PSMA is an antigen expressed on the surface of prostate cancer cells. Multiple radioisotopes are being developed to link with PSMA, including Lu-PSMA-617, which is currently the furthest along in clinical development.

Lu-PSMA is a radiolabeled small molecule that exhibits high-affinity binding to PSMA and delivers therapeutic beta-emitting radiation to tumor sites. Several nonrandomized trials showed promising efficacy and safety of Lu-PSMA in men with pretreated mCRPC.

TheraP was the first randomized trial of patients with mCRPC post-progression on docetaxel-chemotherapy screened with PSMA PET who received Lu-PSMA versus cabazitaxel chemotherapy.

In this study, treatment with Lu-PSMA led to a significantly greater percentage of patients with PSA decline of more than 50% compared with chemotherapy (66% vs 37%, P<0.0001), while preliminary analysis of PSA progression-free survival showed that Lu-PSMA delayed disease progression by 31% compared with cabazitaxel. Data regarding other endpoint is not yet mature.

The toxicity profile also favored Lu-PSMA, with less grade 3/4 events and treatment discontinuations compared with cabazitaxel.

As such, this is a very promising novel compound for this patient population.

In December 2020, the FDA approved Gallium 68 PSMA-11 for PET imaging of PSMA-positive lesions in men with prostate cancer.

Read the study here and expert commentary about the clinical implications here.