Prostate cancer is among the most common cancers in men worldwide, with an estimated 1,600,000 cases and 366,000 deaths annually [23]. In the United States, 11 percent of men are diagnosed with prostate cancer over their lifetime, with the incidence generally rising with age [24]. The overall five-year survival rate is over 98 percent.
After risk stratification, there is a wide variety of treatment options for localized disease, including active surveillance, radical prostatectomy, and definitive radiotherapy. Some males with advanced prostate cancer have evidence of metastatic disease at presentation, while others develop metastatic disease after definitive treatment of localized disease; in some cases, this may be manifested only by an elevation in the serum level of prostate-specific antigen (PSA), termed an isolated biochemical recurrence. Most males initially diagnosed with advanced disease have not received long-term androgen deprivation therapy (ADT), and serum testosterone levels are typically higher than 50 ng/dL. These males are considered to have non-castrate (also called castration-sensitive) prostate cancer. By contrast, males who relapse or recur while receiving ADT are considered to have castration-resistant prostate cancer, although they may still respond to some forms of hormone therapy. Sophie Knipper (Martini-Klinik Prostate Cancer Center, Germany) presented a “Cohort study of patients with oligorecurrent prostate cancer: Oncological outcomes of patients treated with salvage lymph node dissection via PSMA radioguided surgery.” [25] Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) allows the detection of small and/or atypically localized metastatic prostate cancer (PCa) lesions. In a subset of patients with recurrent oligometastatic PCa, salvage surgery with PSMA-targeted radioguidance (PSMA-RGS) may be of value. This cohort study within two tertiary care centers analyzed patients with biochemical recurrence (BCR) after radical prostatectomy (RP) and imaging with PSMA PET who received salvage PSMA-RGS between 2014 and 2020. Kaplan-Meier and multivariable Cox regression models adjusted for various parameters were used to test for BCR-free survival (BFS) and therapy-free survival (TFS) differences. Overall, 364 patients were assessed. At two years of follow-up, the BFS rate was 31.9% and the TFS rate was 58.0%. Higher preoperative PSA (HR: 1.1), a higher number of PSMA-avid lesions on preoperative imaging (HR: 1.2) and multiple (pelvic plus retroperitoneal) localizations (HR: 1.9), and retroperitoneal localization (HR: 2.0) of lesions in PSMA PET imaging were independent predictors of BCR after PSMA-RGS in multivariable analyses. Limitations are the retrospective design and lack of a control group.
As salvage surgery in oligo recurrent PCa currently constitutes an experimental treatment approach, careful patient selection is mandatory based on life expectancy, low PSA values, and the low number of PSMA PET avid lesions located in the pelvis. Further studies are needed to confirm these findings and define the oncological value of salvage surgical procedures in oligo recurrent PCa.
Phuoc T. Tran (University of Maryland School of Medicine, Maryland, USA) presented the Phase 2 SALV-ENZA Trial, a double-blind, randomized study of salvage radiation therapy (SRT) plus enzalutamide or placebo for high-risk PSA-recurrent prostate cancer after radical prostatectomy [26]. They sought to investigate whether enzalutamide (ENZA) treatment, without androgen deprivation therapy, increases freedom-from-PSA-progression (FFPP) when combined with SRT in men with recurrent prostate cancer post-radical prostatectomy (RP). Men with biochemically recurrent prostate cancer after radical prostatectomy were enrolled in a study of SRT and placebo versus SRT and ENZA. The randomization (1:1) was stratified by center, surgical margin status (R0 versus R1), PSA prior to salvage treatment (PSA ≥0.5 versus <0.5 ng/mL), and Gleason score (7 versus 8-10) using a minimization algorithm. Following randomization, patients received either placebo or ENZA 160 mg PO once daily for six months. Following two months of study drug therapy, external beam radiotherapy to 66.6-70.2 Gy was administered to the prostate bed (no pelvic nodes). Eighty-six patients were randomized with a median follow-up of 34 (range 0-52) months. FFPP was significantly improved with ENZA versus placebo; for example, 2-year FFPP was 87.1% versus 68.1%, respectively. Subgroup analyses demonstrate differential benefit (p-value of interaction = 0.031) of ENZA in men with pT3 (HR 0.19, 95%CI 0.05-0.67) vs pT2 disease (HR 1.29, 95%CI 0.34-4.81). The most common adverse events were grade 1-2 fatigue (13% ENZA versus 9%) and urinary frequency (6% ENZA versus 8%). The study showed that SRT plus ENZA monotherapy for men with PSA-recurrent high-risk prostate cancer following RP is safe and delays PSA progression relative to SRT alone. The impact of ENZA on distant metastasis or survival is unknown. The ANZUP 1603 trial studied the efficacy of lutetium PSMA (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC), progressing after docetaxel OS after a median follow-up of 3 years [27]. This group previously reported that patients treated with LuPSMA had significant improvements in PSA and RECIST 1.1 response rates and PFS, as well as fewer grade 3-4 toxicities [28]. In this abstract, the investigators reported results on the secondary endpoint of OS after a median follow-up of three years.
The conclusion from this study is that LuPSMA-based therapy and cabazitaxel showed similar OS, but LuPSMA has fewer AEs and better patient-reported outcomes. If both medications are available, after disease progression on docetaxel, clinicians may consider using LuPSMA therapy first, followed by cabazitaxel chemotherapy."
In addition to reporting on OS, the reanalysis of PSA and radiographic PFS continued to significantly favor the LuPSMA arm with a 38% reduction in the risk of progression. After a median follow-up of 36 months, the OS was similar for lutetium PSMA versus cabazitaxel: 19.1 months for lutetium therapy versus 19.6 months for cabazitaxel therapy, respectively. No additional safety signals were identified with a three-year follow-up.
Another potentially practice-changing study in the field of metastatic prostate cancer was “Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC).” [29] This large Phase 3 international trial included 1,125 patients randomized to receive androgen deprivation plus older antiandrogen such as bicalutamide versus testosterone suppression therapy plus enzalutamide. The unique aspect of the trial was that patients were allowed to receive docetaxel while on study treatment, and as a result, a total of 503 patients received docetaxel.
While a combination of enzalutamide plus testosterone suppression therapy improved survival with a 30% reduction in the risk of death after an additional three years of follow-up, in the subgroup of patients who received concurrent docetaxel, there was no improvement in the OS with enzalutamide. Based on these results, upfront intensification of androgen deprivation therapy with a deeper androgen access inhibitor remains the standard of care and should be offered to all patients with metastatic castration-sensitive prostate cancer. A study presented by Susan Halabi (Duke University Medical Center, North Carolina, USA) assessed the intermediate clinical endpoints as potential surrogates for OS in men with metastatic hormone-sensitive prostate cancer (mHSPC) [30]. The rationale for such analysis stems from the progress in the treatment of castration-sensitive prostate cancer (CSPC), which has significantly improved the OS to seven years or longer.
However, these improvements resulted in Phase 3 clinical trials in hormone-sensitive metastatic prostate cancer taking significantly longer to report OS outcomes. Thus, identifying valid surrogates is critical to expedite results. They analyzed individual patient data from 8,592 patients randomized between 1994 and 2012 from 13 trials in mHSPC and showed that both radiographic PFS (rPFS) and clinical PFS (cPFS) appear to be valid surrogate endpoints for OS. A surrogate threshold effect of 0.82 or higher makes it viable for either rPFS or cPFS to be used as the primary surrogate endpoint for OS in Phase 3 mHSPC trials and would expedite trial conduct. The limitation of this study is its reliance on data from clinical trials that used ADT or ADT and docetaxel as either treatment or control arm. Therefore, validating these intermediate clinical endpoints in clinical trials with drugs having other mechanisms of action is required.