mCRPC: Challenges and treatments
mCRPC treatment landscape
The continuing need for improved mCRPC treatments
Professor Karim Fizazi (Institut Gustave Roussy, Villejuif, France) explains why there is still a pressing need for improved therapies for mCRPC. View transcript.
Has management of mCRPC improved over time?
Professor Fizazi highlights how mCRPC treatments have “dramatically evolved” in the past 20 years and improved outcomes for men with mCRPC. View transcript.
Metastatic prostate cancer epidemiology
Prostate cancer is one of the most prevalent malignant cancers in the world.1
Many people with newly diagnosed prostate cancer have localized disease, and receive prostatectomy or radiation therapy, followed by androgen deprivation therapy (ADT). Prostate cancer cells can become resistant to ADT within 2–3 years, although there is variation in this figure in the published literature.2-10 Cell malignancy can progress, even when serum testosterone is below castrate level.2-10
Because of this loss of hormone sensitivity, some people develop CRPC2-10. CRPC can advance to mCRPC, which is associated with high mortality.10 mCRPC can develop de novo or from metastatic castration-sensitive prostate cancer (mCSPC).2-10
Approximately 700,000 men diagnosed with prostate cancer have metastatic disease, accounting for more than 400,000 deaths globally per year.11 This mortality is expected to more than double by 2040.12 However, regional decreases in mortality-to-incidence ratios for prostate cancer (1990–2019) highlight improved outcomes, efficient screening, and therapeutic strategies.13 Despite the treatment options available for mCRPC, the disease remains incurable.
Figure 1 shows incidence and prevalence data of mCRPC per 100,000 enrollees in a US managed-care, insured population (2009–2018).14
Figure 1. Incidence and prevalence of metastatic castration-resistant prostate cancer (mCRPC) per 100,000 enrollees, 2009–2018, in a US managed-care, insured population.14 Reproduced from Wallace et al.14 with permission from Springer Nature. Incidence of mCRPC was relatively constant between 2009–2018, while prevalence increased.
Brief overview of prostate cancer biology
Some evidence points to persistent inflammation and infection stimulating prostate carcinogenesis through oxidative stress, and production of reactive oxygen species that cause DNA damage and recruitment of mutated cells.15-17
Through inflammation, the prostate is enriched for proliferative luminal epithelial cells that are vulnerable to epigenetic and genomic chromatin alterations, leading to prostatic intraepithelial neoplasia and malignant change.15-17
Prostate cancer largely relies on alterations in the androgen receptor gene (AR) pathway.2-9 mCRPC shows AR changes through amplification or gain-of-function mutations, increased transcription of AR, or increased AR signaling.15-17
Progression to mCRPC is associated with dysregulation of genes involved in growth control and genetic stability (Figure 2).15-17
Figure 2. Somatic mutations, prognostic, and predictive biomarkers in metastatic prostate cancer.17 Reproduced from Sandhu et al.17 with permission from Elsevier. AR-V7, AR splice-variant 7; CRPC-NE, castration-resistant neuroendocrine prostate cancer; ctDNA, circulating tumor DNA; CTC, circulating tumor cell; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer.
Discovery of molecular markers predictive of treatment responses has stimulated more personalized treatments for mCRPC2-9
The evolving treatment landscape for mCRPC
What key factors influence management of mCRPC? Professor Axel Merseburger (University Hospital Schleswig-Holstein, Campus Lübeck, Germany) notes multiple interacting factors are involved. View transcript.
Biochemical relapse after local treatment for prostate cancer can progress to metastasis or the development of CRPC.2-9 Once mCRPC is identified, there are several first-line treatment options (Figure 3).2-9
Figure 3. Treatment landscape for advanced prostate cancer.18 Reproduced from Mateo et al.18 with permission from Springer Nature. Some approved treatments refer to the USA only (see “USA” in figure). *Olaparib is also approved in the EU for mCRPC, combined with abiraterone and prednisone or prednisolone in patients for whom chemotherapy is not clinically indicated.19 Yellow boxes show approved treatments, irrespective of molecular profiling. Red boxes refer to biomarker-based treatments, approved only for molecularly defined subgroups with mCRPC. ADT, androgen deprivation therapy; ARSI, androgen-receptor signaling inhibitor; HR, hormone receptor; mCRPC, metastatic castration-resistant prostate cancer; MMR, mismatch repair deficiency; PARP, poly adenosine diphosphate-ribose polymerase; PSA, prostate-specific antigen.
Recommended management options for mCRPC include:2-9
- The androgen-synthesis inhibitor abiraterone
- AR-signaling inhibitors (ARSI; also called novel hormonal agents) enzalutamide, apalutamide, and darolutamide
- Cytotoxic chemotherapy agents (docetaxel, cabazitaxel)
- Radiopharmaceuticals (radium-223, 177Lutetium-PSMA-617)
- Immunotherapies (sipuleucel-T)
The main clinical goals of mCRPC management are to delay disease progression and palliate symptoms.2-9 While extending overall survival (OS) is typically the priority for patients with mCRPC, a US patient preference survey revealed that some patients are willing to forgo 1.9 months of OS for elimination of moderate nausea and 3.3 months of OS for a reduction in fatigue from severe to mild.20
ESMO and NCCN guidelines for mCRPC
Figure 4 shows a timeline of treatments for mCRPC based on the year of the pivotal trial.21
Figure 4. Timeline of treatments for mCRPC, based on the year of the pivotal clinical trial. Image licensed under CC-BY-NC 3.0 from Turco et al.21 *Approval from the European Medicines Agency (EMA) withdrawn; not available in Europe.22 †Symptomatic, bone only, LN <3 cm, visceral metastases excluded. ‡Olaparib was approved for mCRPC as monotherapy in the presence of germline or somatic BRCA1/2 mutations after progression on a new hormonal agent, or combined with abiraterone and prednisone or prednisolone when chemotherapy is not clinically indicated.19,23
Docetaxel (TAX 327; SWOG 99-16)
Docetaxel improved overall survival (OS) compared with mitoxantrone (18.9 months vs 16.5 months; HR, 0.76; 95% CI, 0.62–0.94; P=0.009), and in combination with estramustine compared with mitoxantrone (17.5 months vs 15.6 months; HR, 0.8; 95% CI, 0.67–0.97; P=0.02).24,25 Grade 3 or 4 neutropenic fevers, nausea and vomiting, and cardiovascular events were more common in patients on docetaxel and estramustine than patients on mitoxantrone and prednisone.25 In 2004, docetaxel became the standard-of-care first-line treatment for mCRPC.24,25 Docetaxel is approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for mCRPC.26,27
Cabazitaxel (TROPIC; CARD; FIRSTANA)
In the phase 3 TROPIC trial, cabazitaxel was superior to mitoxantrone for OS in people with mCRPC progressing on, or after, docetaxel (15.1 months vs 12.7 months; HR, 0.7; 95% CI, 0.59–0.83; P<0.0001). The most common grade ≥3 adverse events (AE) were neutropenia (cabazitaxel, 303 [82%] patients vs mitoxantrone, 215 [58%]) and diarrhea (23 [6%] vs one [<1%]).28
In the phase 4 CARD trial, the median OS for cabazitaxel was 13.6 months, and 11.0 months with the ARSI (HR, 0.64; 95% CI, 0.46–0.89; P=0.008). AE of grade ≥3 occurred in 56.3% of patients on cabazitaxel, and in 52.4% on an ARSI.29 In the phase 3 FIRSTANA trial, cabazitaxel did not demonstrate superiority for OS compared with docetaxel in patients with chemotherapy-naive mCRPC. Rates of grade 3 or 4 treatment-emergent adverse events (TEAE) were 41.2%, 60.1%, and 46.0% for cabazitaxel C20, C25, and D75, respectively.30 Cabazitaxel is FDA and EMA indicated for the treatment of mCRPC.31,32
Abiraterone (COU-AA-301; COU-AA-302), enzalutamide (AFFIRM; PREVAIL)
Pivotal phase 3 trials with abiraterone (COU-AA-301; COU-AA-302) and enzalutamide (AFFIRM; PREVAIL) showed improved OS or radiographic progression-free survival (rPFS) for mCRPC following treatment with docetaxel, and in patients naive to docetaxel:33-36
- COU-AA-301: OS was longer for abiraterone acetate–prednisone than for placebo–prednisone (14.8months vs 10.9 months; HR, 0.65; 95% CI, 0.54–0.77; P<0.001). Fluid retention, hypertension, and hypokalemia were more frequent for abiraterone acetate–prednisone than placebo–prednisone.33
- COU-AA-302: Median rPFS was 16.5months for abiraterone–prednisone and 8.3 months for prednisone alone (HR for abiraterone–prednisone vs prednisone, 0.53; 95% CI, 0.45–0.62; P<0.001). Over a median follow-up period of 22.2 months, OS improved for abiraterone–prednisone (median not reached vs 27.2 months for prednisone alone; HR, 0.75; 95% CI, 0.61–0.93; P=0.01). Grade 3 or 4 AEs and abnormalities on liver-function testing were more common with abiraterone–prednisone.34
- AFFIRM: Median OS was 18.4months (95% CI, 17.3 to not yet reached) for enzalutamide, versus 13.6 months (95% CI, 11.3–15.8) in the placebo group (HR for enzalutamide, 0.63; 95% CI, 0.53–0.75; P<0.001). Rates of fatigue, diarrhea, and hot flashes were higher for enzalutamide.35
- PREVAIL: rPFS at 12months was 65% for enzalutamide and 14% for placebo (81% risk reduction; HR for enzalutamide group, 0.19; 95% CI, 0.15–0.23; P<0.001). Fatigue and hypertension were the most common AEs associated with enzalutamide.36
Abiraterone is FDA and EMA approved for mCRPC.37,38
Radium-223 (ALSYMPCA)
In ALSYMPCA, radium-223 reduced the risk of death by 30% compared with placebo in symptomatic people with mCRPC (predominant bone metastases) who had received, were ineligible to, or had refused to receive docetaxel (HR, 0.7; 95% CI, 0.58–0.83; P<0.001). Radium-223 was associated with lower myelosuppression rates and fewer AEs than placebo.39 Radium-223 was FDA and EMA approved for mCRPC in 2013.40,41
177Lutetium-PSMA-617 (VISION)
177Lutetium-PSMA-617 improved OS in people with prostate-specific membrane antigen (PSMA)-positive mCRPC previously treated with at least one ARSI, and one or two taxane regimens, compared with the protocol that permitted standard care alone (15.3 months vs 11.3 months, HR, 0.62; 95% CI, 0.52–0.74; P<0.001). AE rates of grade ≥3 were higher with 177Lu-PSMA-617 than without (52.7% vs 38.0%); quality of life was not adversely affected.42 177Lutetium-PSMA-617 is approved by the FDA and EMA for mCRPC.43,44
Olaparib (PROFOUND)
In the phase 3 PROFOUND study, the poly adenosine diphosphate-ribose polymerase inhibitor (PARPi) olaparib reduced the risk of death by 31% in people with mCRPC who had a gene alteration in BRCA1, BRCA2, or ATM, and whose disease had progressed during previous treatment with enzalutamide or abiraterone (HR, 0.69; 95% CI, 0.50–0.97; P=0.02). Anemia and nausea were the most common AEs in patients receiving olaparib.45 Olaparib is FDA and EMA indicated for mCRPC.19,23
Talazoparib (TALAPRO-2, 3)
In the phase 3 TALAPRO-2 clinical trial, median rPFS was significantly improved in the talazoparib plus enzalutamide group versus placebo plus enzalutamide group (not reached vs 21.9 months, respectively; HR, 0.63; 95% CI, 0.51–0.78; P<0.001). In the talazoparib group, the most common TEAEs were anemia, neutropenia, and fatigue; the most common grade 3–4 AE was anemia (185 [46%] of 398 patients); 33 (8%) of 398 patients discontinued talazoparib due to anemia.46 Talazoparib is approved by the FDA only in combination with enzalutamide for HRR gene-mutated mCRPC, and by the EMA for patients with mCRPC in whom chemotherapy is not clinically indicated.47,48 TALAPRO-3 data are expected for publication on clinical trial registries later in 2024.49
Rucaparib (TRITON 2)
The approved PARPi rucaparib was evaluated in the phase 2 TRITON 2 study.50-52 In TRITON 2, rucaparib showed an objective response rate of 43.5% and a prostate-specific antigen response rate of 54.8% in 115 people with mCRPC with BRCA1 or BRCA2 mutations who progressed after at least one ARSI and one taxane-based chemotherapy. The most frequent grade ≥3 TEAE was anemia (25.2%; 29 of 115 patients). 52
Sipuleucel-T (IMPACT)
Sipuleucel-T, an autologous cellular immunological agent, improved OS compared with placebo in the phase 3 IMPACT study (25.8 months vs 21.7 months; HR, 0.78; 95% CI, 0.61–0.98; P=0.03). AE were more frequently observed for sipuleucel-T than placebo, including headache, chills, and fever.53
At the request of the manufacturer, EMA withdrew marketing authorization for sipuleucel-T because of logistical challenges associated with production.22 Therefore, sipuleucel-T is not available in Europe and is only approved by the FDA.54
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