Systemic Therapy for Very High Risk to Oligometastatic Prostate Cancer

By GU Oncology Now Editors - Last Updated: January 18, 2022

The latest developments in systemic therapy for very high-risk localized and oligometastatic prostate cancer were reviewed during the 2021 ASTRO annual meeting by Alicia K. Morgans, MD, MPH, genitourinary medical oncologist and Medical Director of the Survivorship Program at Dana-Farber Cancer Institute, Boston, MA. Multidisciplinary treatment, including a combination of systemic therapy, radiation, and surgery is offering patients with high-risk disease new hope for long-term disease control and potential cure, Dr Morgans declared.

The latest National Comprehensive Cancer Network (NCCN) Clinical Practice Guideline on prostate cancer (version 1.2022, issued September 2021)1 defines high-risk and very high-risk in clinically localized disease by clinical/pathological features, including clinical stage ≥cT3a, Gleason Grade Group 4-5, and PSA >20 ng/ mL, Dr Morgans noted. “There are multiple formulations issued by other organizations including the American Society of Clinical Oncology (ASCO), the American Urological Association (AUA), and the RTOG, so it is important to remember and think about which mode we are using when we are identifying our patients, if we are going to enroll them in clinical trials, Dr Morgans stressed.

Another important point to consider in this population is where PET scans fit into their assessment, she noted. The NCCN guideline incorporates gallium (Ga) 68 PSMA-11 and piflufolastat F 18 into its guidance and suggests that these imaging modalities be considered for bone and soft tissue imaging. Because of their increased sensitivity and specificity, the NCCN guideline panel decided that conventional imaging was not a necessary prerequisite to identify lesions in this population. This applies to high-risk and very high-risk populations.

More information is becoming available as to how PSMA PET imaging can cause stage migration into an oligometastatic state, Dr Morgans noted. She pointed out that in the proPSMA trial, there were two instances of stage migration (negative CT, positive PSMA PET/ CT) recorded with Ga 68 PSMA-11 PET/CT scans in the staging algorithm for men with high risk localized disease.2 It is important to recognize that these patients would meet the criteria for high-risk/very high-risk disease, according to studies of how best to care for these patients, Dr Morgans emphasized.

The studies that Dr Morgans reviewed were all based on conventional imaging. “So in our multidisciplinary approaches and our tumor boards, we need to have conversations about how to use the data that we have from studies to apply and think about how transferring these patients into an oligometastatic state may affect them,” she advised. “We would not want to lose the opportunity to potentially intensify treatment and cure patients if that is possible,” she cautioned, noting that “his is still being understood.”

The NCCN guideline focuses on approaching high- or very high-risk patients with radiation combined with systemic therapy or radical prostatectomy (RP) in specifically identified and motivated patients. Initial studies of neoadjuvant systemic therapies in men with high- or very-high risk localized prostate cancer focused on identifying the effect of neoadjuvant ADT alone. Many trials made use of endpoints around negative surgical margins and prostate-specific antigen (PSA) responses, rather than endpoints that were more meaningful to patients, such as biochemical recurrence (BCR) and metastasis-free survival (MFS). The reason for this was that these types of endpoints take more time and require greater numbers of patients to show benefit, Dr Morgans explained.

Some contemporary neoadjuvant systemic strategies around surgery have focused on intensified therapy such as ADT plus abiraterone or enzalutamide, or both, and have attempted to use endpoints that are more meaningful to patients, such as biochemical recurrence (BCR), and focused on pathologic complete response (PCR) and minimum residual disease (MRD).

An analysis of three recent neoadjuvant trials in high- or very-high risk patients (TAPS,3 Neo-Abi,4 and Neo-Enza5), showed that ADT plus abiraterone, enzalutamide, or both, was associated with PCR in 4-10%,6 she noted, stressing the importance of having a consistent central pathological review for this endpoint. The other endpoint, MRD, defined as tumor in the RP specimen measuring ≤0.5 cm, occurred in 17-30% of patients. Dr Morgans explained that whereas 23 of the 72 patients in the trials had BCR (median time to BCR 5.1 years), none of the 11 patients with MRD had BCR.

The combination of ADT plus apalutamide is being investigated in perioperative treatment of high-risk patients with locally advanced disease in the phase 3 PROTEUS trial (NCT03767244) . The co-primary endpoints of this trial are PCR and MFS.

Neoadjuvant chemotherapy has also been investigated in the surgical population high and very high-risk prostate cancer, she explained. Dr Morgans referenced the PUNCH trial (CALGB 90203/Alliance), which randomized high- risk prostate cancer patients to 6 cycles of docetaxel plus ADT before RP or upfront RP.6 Unfortunately, although the results of this trial initially appeared to favor surgery, there was no significant difference between the cohorts with regard to 3-year biochemical PFS (HR 0.89 vs 0.84, P=0.11). However neoadjuvant therapy was associated with improved MFS (HR 0.70) and overall survival (OS) (HR 0.61). Dr Morgans explained that although this negative trial could not be incorporated into guidelines, interest in the neoadjuvant approach has continued. “Of course, chemotherapy comes at a greater cost than hormonal-based therapies, so this is not something that is necessarily being pursued in further studies, she added.

Studies of adjuvant approaches include the Veterans Affairs Cooperative Studies Program study #553 study, which evaluated the role of adjuvant docetaxel chemotherapy added to standard of care in patients at high risk for relapse after prostatectomy.7 Dr Morgans recalled that the study failed to enroll a sufficient number of patients to be randomized to the chemotherapy, a familiar situation to medical oncologists, she commented. Based on the limited enrollment (298 of planned 636 patients), the study showed no clinical benefit associated with neoadjuvant chemotherapy.

Identifying patients by clinical findings in the VA #553 trial may have resulted in a more heterogeneous population with respect to risk, Dr Morgans suggested. In order to better identify the highest risk patients, Dr Morgans and the ECOG-ACRIN Cancer Research group are employing the Decipher Prostate genomic classifier (Veracyte) in the ongoing ERADICATE trial (NCT04484818), which is investigating the addition of darolutamide to ADT after RP. The trial is enrolling patients with Decipher Prostate score >0.6, who are randomized to 12 months’ treatment with ADT or ADT plus darolutamide and followed for MFS, the study primary endpoint. This study is expected to complete in 2028.

The role of intensified systemic therapy has been investigated in radiation trials, including the RTOG 0521 trial, which evaluated the role of adjuvant chemotherapy in high-risk patients with localized prostate cancer, demonstrated improved 4-year OS from 89% to 93% OS (HR 0.69) associates with administration of docetaxel after ADT plus radiation therapy.8 There was some controversy about the statistical interpretation of these trial results plus there was greater toxicity associated with docetaxel, Dr Morgans recalled. Nonetheless, this regimen is included in the latest NCCN guideline as a recommendation for high-risk patients who will understand and choose to get adjuvant chemotherapy after treatment of their localized disease. This requires shared decision making for patients, Dr Morgans stressed. One of the most exciting recent developments, Dr Morgan said, came from data on the M0 non-metastatic patient population in the STAMPEDE trial, which were presented at the 2021 ESMO annual meeting.9 These patients were treated with ADT plus abiraterone with or without enzalutamide in addition to RT over 2 years.

She explained that most of these patients had very high-risk localized disease and the others had early relapsing disease. The results showed the benefit of ADT plus abiraterone compared with ADT alone, with improvement in 6-year MFS from 69% to 82% (HR 0.53, 95%CI 0.44-0.64, P=2.9 × 10-11) and in 6-year OS from 77% to 86% (HR 0.60, 95%CI 0.48-0.73, P=9.3 × 10-7). So “pretty clear,” benefit, Dr Morgans remarked, although the research has yet to be published in a peer-reviewed journal, she noted.

Dr Morgans concluded by reiterating the importance of considering a multidisciplinary approach to treating patients with high-risk prostate cancer potentially employing systemic therapy, radiation and surgery. She stressed the need for accurate risk stratification that may include PET scans in this “new era” of imaging, “This is critical to achieve maximal disease control and reduce complications,” she stated. “I think we all want to understand, as we are migrating patients’ stages, how to best apply the data that we have acquired from conventional imaging, and we don’t want patients to lose that opportunity for cure.” Neoadjuvant and adjuvant systemic treatments are still being evaluated in combination with local treatment, she noted. As suggested by the STAMPEDE analysis, ADT plus abiraterone in men with very high risk locally advanced disease appears to prolong MFS and OS in men compared with ADT alone and may be a new standard of care, she suggested.

Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.


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