Clinical Cases in Prostate Cancer: Highlighting Four Key Advances
A Panel Discussion from the Total Health 2023 Community Cases Tampa Conference
September is Prostate Cancer Awareness month, and at the recent Total Health Community Cases Conference held in Tampa, Florida, a panel discussion on Genitourinary Cancers featured case presentations focusing on different clinical scenarios in prostate cancer, with a focus on four major advancements in the field over the last two years. The discussion was moderated by Dr Jingsong Zhang, MD, PhD, from the Moffitt Cancer Center, and also featured Dr Juskaran Chadha, DO, and Sarah Raymond, PA, from the Moffitt Cancer Center.
Overview
Dr Zhang reviewed the general course in prostate cancer treatment, with the first major question being staging of the cancer. For most patients diagnosed with localized prostate cancer, options include surgery (radical prostatectomy) or radiation therapy (RT), and about one third of patients will develop a recurrence after their initial treatment. Unlike many other cancers, there is a definitive clinical tumor marker in prostate cancer, namely prostate specific antigen, or PSA. For example, after surgery for prostate cancer, PSA level should go down to zero, whereas if PSA starts rising after surgery, this is an indicator that the patient’s cancer has returned. For a rising PSA in the absence of a detectable clinical recurrence on imaging, this is termed a “biochemical recurrence” and Dr Zhang emphasized this as a ‘grey zone’ for treatment, as currently there is a lack of clear guidance for how such patients should be managed. Gleason score is another clinical parameter for prostate cancer staging based on its microscopic appearance on biopsy; Gleason score sums range from 6 through 10, with higher numbers indicating worse prognosis.
Because prostate cancer growth depends on the presence of sex hormones (androgens), androgen deprivation therapy (ADT), or “chemical castration” remains a cornerstone of treatment. There are a number of agents available for ADT, including luteinizing hormone-releasing hormone (LHRH) analogues such as leuprolide which reduce testosterone levels, abiraterone acetate (used in combination with prednisone) which blocks production of testosterone by the adrenal glands and cancer cells, as well as agents that block the cellular action of androgens such as bicalutamide, apalutamide, darolutamide, and enzalutamide. A significant subset of patients may present with disease that is already metastatic at time of diagnosis (termed “de novo”metastatic prostate cancer) and this is indicative of more aggressive disease. For these patients, combined ADT with LHRH analogues and androgen signaling inhibitors is the current standard of care. Despite the initial response, however, their prostate cancers will eventually progress to the metastatic castration-resistant stage, or mCRPC. which has a survival of about 3 to 5 years from the time of resistance.
One of the recent advancements that the panel noted was the use of prostate-specific membrane antigen positron emission tomography (PSMA-PET) scanning as a means for prostate cancer staging. The purpose of PSMA-PET is to help stage prostate cancer patients with intermediate to high risk for metastases, to find early metastatic sites that may be amenable for treatment in the case of a biochemical recurrence, and lastly, to identify patients with early metastatic (M1) prostate cancer who may be candidates for lutetium-177-PSMA-617 (pluvicto), a new radioactive therapy for patients with mCRPC. Importantly, Dr Zhang noted there is no clear guidance at present on how to use PSMA-PET scanning to determine the response to treatments like ADT.
Case 1
In the first case, the patient considered was a 63-year old with high risk features, including a PSA level of 33, invasion of the left seminal vesicle, and a Gleason score of 9 for his prostate cancer. The patient underwent a PSMA-PET scan which showed uptake in the prostate and a left pelvic lymph node. As such, the patient’s disease was classified as clinical stage IV, T3b, N1 (lymph node involvement), and M0 (no metastases detected). Dr Chadha thought the most appropriate treatment option for this patient would be combined ADT with leuprolide, in addition to abiraterone acetate and prednisone, followed by definitive RT to the prostate gland, based upon results from the STAMpede trial. Another option, he noted, would be combined ADT with leuprolide, and the novel anti-hormone agent apalutamide based on findings of another trial, TITAN. Dr Chadha thought that radical prostatectomy (removal of the prostate) with lymph node dissection was not recommended due to the risk for significant complications in this younger patient, such as urinary incontinence and erectile dysfunction.
The optimal treatment for this patient was based on the results of the STAMpede trial, which aimed to optimize or intensify ADT when used in combination with RT. The results of this trial showed that adding 2 years’ treatment with abiraterone to 3 years of ADT significantly improved metastasis-free and overall survival (OS) for men with high risk disease without metastasis (i.e., ‘M0’ patients), and have established this treatment as the current standard of care. Dr Zhang noted there was also some survival benefit observed in the STAMpede trial of adding definitive RT to the prostate for patients with “low volume” M1 disease, defined as less than 5 metastatic sites on scanning (for example, a solitary bone mass in the rib or spine). A subsequent study (PEACE-1), however, failed to confirm these findings, and the results for this low volume M1 patient population are less clear at present.
Case 2
For the second case, the panel considered a 77-year old practicing physician presenting with severe lower back pain. His MRI shows a fracture due to lytic bone metastases, his PSA is >5000 mg/mL, and his pathology shows prostate adenocarcinoma on biopsy, with no significant mutational findings on genomic analysis by next generation sequencing (NGS). Dr Chadha noted this is a patient with diffuse bone metastases (more than 3 bone lesions), and de novo metastatic disease. He noted there were no high risk molecular features based on his NGS profile, and that abiraterone/prednisone with ADT would be a reasonable treatment option. Dr Zhang agreed, noting that adding chemotherapy to the regimen would not offer much benefit and only cause additional fatigue with his subsequent RT. After starting this treatment, Dr Zhang noted that the patient had an 80% reduction in his PSA (a very good response) with an improvement in his pain from metastases. After approximately 1 year, he elected to take a break from his abiraterone therapy due to side effects and financial concerns, and he was continued on leuprolide monotherapy. After about 1 year on leuprolide monotherapy his PSA began to rise again, however there were no new lesions and his bone metastases remained stable. At 5.4 years into therapy, he remains on leuprolide monotherapy and his PSA remains under 1.0. Dr Zhang reviewed the poor prognostic factors in this case, specifically the de novo high volume disease, and having symptoms (pain) at his initial presentation. The favorable prognostic factors, however, included his good PSA response to ADT, a lack of visceral (i.e., liver, lung) metastases, and no significant mutational findings or aggressive features on NGS. Some of the main questions and answers the panel addressed for a case such as this, with M1 mCSPC, are summarized in Box 1.
Box 1. Questions and Answers in Managing M1 CSPC
Q: How do we determine patient risk in mCSPC (risk stratification)?
A: Risk is still based on clinical features, but the PSA response to ADT (i.e., reduction in PSA level) at month 7 has the most prognostic data: Good PSA response = better prognosis.
Q: Do all patients with mCSPC need combined ADT with abiraterone, enzalutamide, apalutamide?
A: Combined ADT may not be necessary for all mCSPC patients if they have a rapid PSA response to standard ADT “You can save those treatments for another day…”
Q: For mCSPC patients on newer hormonal agents, is treating until progression the right approach?
A: Continued treatment may not be necessary if the patient achieves a PSA level of < 0.2.
Q: When should we use triple therapy (LHRH analog+ new hormonal agent + docetaxel) for M1 CSPC?
A: Triple therapy is most appropriate for selected patients with liver metastases, or those with symptomatic de novo metastatic cancer at presentation.
Case 3
The third case the panel considered highlighted another recent advancement in prostate cancer treatment, the use of targeted treatment for patients with M1 castration sensitive prostate cancer (mCRPC), specifically poly (ADP-ribose) polymerase (PARP) inhibitor drugs, which have shown efficacy in those patients with mCRPC who have alterations in DNA homologous recombination repair (HRR) genes, including BRCA1/2(approximately 25% of mCRPC patients). Phase III studies have shown that the efficacy of PARP inhibitors, alone or in combination with agents like abiraterone or enzalutamide for patients with M1 CRPC and HRR gene alterations (Box 2). Another option for patients with DNA mismatch repair deficiency (dMMR), those with microsatellite instability (MSI)- “high” status, or a high tumor mutational burden (TMB) above 10 mutations/mb (< 3% mCRPC patients), is immunotherapy with the anti-programmed death ligand (PD-L1) agent pembrolizumab (Box 2). Dr Zhang noted that testing for such molecular alterations is especially important, in order to identify patients who might benefit from these targeted therapies.
Box 2. Trials of Targeted Treatments in mCRPC
PARP Inhibitors for M1 CRPC: ·
Olaparib as monotherapy for M1 CRPC with DNA HRR gene alterations (Phase III Profound Trial)
Olaparib in combination with abiraterone and prednisone for BRCA1/2 mutated M1 CRPC (Phase III Propel Trial)
Rucaparib for BRCA1/2 mutated M1 CRPC (Triton 2 and Triton 3 Trials)
Talazaprib plus enzalutamide for M1 CRPC with HRR gene alterations (Phase III Talapro 2 Trial)
Niraparib in combination with abiraterone and prednisone for BRCA-mutated M1 CRPC (Phase III Magnitude Trial)
Immunotherapy for M1 CRPC
Pembrolizumab for patients with DNA mismatch repair deficiency (dMMR), microsatellite instability (MSI) high status or tumor mutational burden (TMB) above 10/mb
The panelists considered a third case of a patient who had previously undergone radical prostatectomy for his stage III T3aN0M0, Gleason score 7 prostate cancer, and he had also received adjuvant RT. Over a ten year period, he had undergone ADT and several changes in treatment, including chemotherapy with docetaxel, for biochemical recurrences and progression to M1 CRPC. At his most recent visit, his PSA is 7.6, with evidence of minor progression at a pelvic mass, and the panel considered treatment options. Dr Chadha thought that obtaining a biopsy of the mass would be a reasonable option, to determine if he is a candidate for targeted treatment of his advancing disease. Dr Zhang agreed, noting that, in fact, this patient’s cancer was much more aggressive than originally expected, with a molecular profile seen in < 1% of prostate cancer. NGS analysis of his biopsy specimen showed multiple high-risk abnormalities including BRCA2 mutation, MSI high status, androgen receptor (AR) mutation, loss of PTEN and TP53, and high TMB (15 mutations/mb). Subsequent treatment with Olaparib showed a limited response of only 7 months, and there was no further response with addition of abiraterone to Olaparib (likely due to his AR mutation). The patient also failed subsequent treatments including cabazitaxel, pembrolizumab, and carboplatin, and later died from his progressive disease. Dr Zhang noted that the case illustrates the rarer subset of prostate cancers that are highly treatment resistant, and the benefit of doing NGS testing to better identify any high risk molecular features, if present.
Case 4
In the last case, the panelists considered a 57-year old man presenting with de novo metastatic prostate cancer to the liver. On staging, he was found to have both liver and bone metastases, and the liver lesions showed prostate cancer on biopsy. He was not shown to have any notable mutations in HRR genes on genomic testing and had low tumor mutational burden. He received continuous ADT with leuprolide as well as upfront chemotherapy with docetaxel. He then progressed and was initiated on enzalutamide for mCRPC. His PSA levels initially decreased markedly on this treatment, but then began rising again, however, his scans showed overall stable liver and bone metastases (i.e., an initial response followed by a biochemical recurrence). Dr Chadha thought, based on his otherwise stable metastases and a lack of aggressive tumor mutations, the best treatment option for this patient would be cabazitaxel, a chemotherapy which is indicated (in combination with prednisone) for patients who have received prior docetaxel treatment. Dr Zhang noted that, despite his mutational findings, his disease is likely very aggressive because he had liver metastases at initial presentation. He noted that liver metastases occur in < 10% of stage IV prostate cancers and can be very difficult to manage.
Dr Zhang reviewed results from the VISION trial of Lutetium-177 (177Lu-PSMA 617) which demonstrated improved radiographic progression-free survival (rPFS) and overall survival (OS) with 177Lu-PSMA-617 for patients with mCRPC who had received prior chemotherapy treatment with docetaxel. He also noted that the trial showed a relationship between the overall PSA response and rPFS, such that for patients with a PSA decline of > 90%, the rPFS was 20.3 months, whereas for those with no decline in PSA, the rPFS was 3.6 months. As such, he noted that a lack of a PSA response after 2 doses (12 weeks) of 177Lu-PSMA 617 is an early indicator that the patient is not responding, and the treatment should therefore be changed to avoid significant adverse events like thrombocytopenia. With regard to the case in question, Dr Zhang noted that following the patient’s first dose of 177Lu-PSMA-617, there was a rapid doubling of PSA (indicative of no response) with a similar increase in PSA after the second dose; this was followed by progression of his bone metastases and death, underscoring the importance of PSA monitoring when using this novel agent in mCRPC.
Quick Summary: Four Key Advances in Prostate Cancer
Approval of prostate-specific membrane antigen-positron emission tomography (PSMA-PET) scanning for staging in intermediate-high risk prostate cancer.
Early detection of metastases with PSMA-PET in patients with PSA ‘biochemical’ recurrence can identify patients for radioligand therapies, such as 177Lu-PSMA 617
Combined androgen deprivation therapy (ADT) with “next generation” androgen receptor (AR) pathway inhibitors (abiraterone, enzalutamide, apalutamide, darolutamide) for patients with metastatic (M1) castration-sensitive prostate cancer (CSPC).
Targeting DNA damage repair deficiency in metastatic (M1) CRPC with Poly (ADP-ribose) polymerase (PARP) inhibitor drugs, alone or in combination, for patients with homologous recombination repair (HRR) gene mutations.
Radioligand therapy targeting prostate-specific membrane antigen (PSMA) using Lutetium-177 (177Lu-PSMA 617) as an option for mCRPC patients with prior docetaxel treatment.
Monitoring of PSA response following 2 doses of 177Lu-PSMA 617 is important to identify non-responders.
Speaker Disclosure Information: Dr Zhang lists the following disclosures: Advisory board or Speaker bureau:AstraZeneca, Astellas, Bayer, Dendreon, Sanofi, Pfizer.
You can see the full case discussion from 2023 Community Cases Tampa here: